Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 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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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

1.

WHOPAR Part 4

March 2023

NAME OF THE MEDICINAL PRODUCT[TB168 trade name]†

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains:
Rifampicin 150 mg
Ethambutol hydrochloride 275 mg
Isoniazid 75 mg
Pyrazinamide 400 mg
Excipients with potential clinical effect
Each tablet contains 0.325 mg sunset yellow colorant
For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Light buff coloured biconvex capsule shaped film-coated tablets, with plain surface on both sides.
The tablet should not be divided.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications[TB168 trade name] is a combination medicine for the initial treatment of 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

For oral use.
Posology
Treatment regimens should follow the most recent WHO treatment guidelines, supplemented by otherauthoritative guidelines.
Typical recommended doses for initial (intensive phase) treatment in adults and children weighing more than
25 kg:†

Patients’ weightDose

25–29.9 kg

2 tablets once daily

30–34.9 kg

3 tablets once daily

35–64.9 kg

4 tablets once daily

65 kg and over

5 tablets once daily

Trade names are not prequalified by WHO. This is the national medicines regulatory agency’s responsibility.
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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

Initial (intensive phase) treatment with [TB168 trade name] is normally given for 2 months, which is
generally followed by treatment with isoniazid and rifampicin (continuation phase). The duration oftreatment depends on the regimen selected.
[TB168 trade name] should not be used for intermittent treatment regimens.
[TB168 trade name] should be taken as a single daily dose on an empty stomach (at least 1 hour before or 2hours after a meal). Absorption may be reduced if taken with food e.g. to improve gastrointestinal tolerance.
If one of the active ingredients of this medicine needs to be discontinued or if the dose needs to be reduced
then separate preparations of the ingredients (ethambutol, isoniazid, pyrazinamide, and rifampicin) should be
used.
Supplementation with pyridoxine (vitamin B6) may be considered, especially in malnourished individuals,
children and those living with HIV (see section 4.4).
Renal impairment
Since dose adjustment may be necessary in patients with renal impairment (creatinine clearance≤ 50 mL/minute), it is recommended that separate preparations of ethambutol, isoniazid, pyrazinamide, andrifampicin be used (see section 4.4).
Hepatic impairment
Limited data indicate that the pharmacokinetics of isoniazid and rifampicin are altered in patients with
hepatic impairment. Therefore, patients with hepatic impairment should be closely observed for signs of
toxicity. [TB168 trade name] must not be used in patients with a history of acute liver disease (see section
4.3).
Children, adolescents and patients weighing less than 25 kg[TB168 trade name] is not suitable for patients with a body weight below 25 kg, since appropriate dose
adjustments cannot be made. Alternative formulations should be used.
Elderly
No special dosage regimen is necessary, but hepatic or renal insufficiency should be considered.
Supplementation of pyridoxine (vitamin B6) may be useful.
Interruption of treatment
If treatment with [TB168 trade name] is interrupted for any reason including non-adherence, the productshould not be used for resuming treatment. Ethambutol, isoniazid, pyrazinamide and rifampicin must be
administered separately for the resumption of treatment because rifampicin needs to be reintroduced at alower dose. Official guidance should be consulted on the resumption of treatment with tuberculosis
medicines.
4.3

Contraindications

Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or any of the excipients listed in section
6.1.
A history of drug induced hepatitis and acute liver disease, regardless of its cause.
Porphyria.
Acute gouty arthritis.
Severe renal impairment (creatinine clearance less than 30 mL/minute) (see section 4.4).
Concomitant use with voriconazole or with protease inhibitors for HIV or hepatitis C virus infection (seesection 4.5).

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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

4.4

WHOPAR Part 4

March 2023

Special warnings and precautions for use

Warnings
Where the patient’s acetylation phenotype is known, patients with extremely fast or extremely slow
acetylating capability should receive the four components separately in order to facilitate dose adjustment ofisoniazid.
In exceptional cases, rifampicin may provoke severe hypersensitivity reactions such as thrombocytopenia,
purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock or renal failure. [TB168 trade name]should be withdrawn immediately if severe acute hypersensitivity reactions occur. Patients who develop suchreactions must never again be treated with rifampicin.
[TB168 trade name] should also be withdrawn if other signs of hypersensitivity appear, such as fever or skinreactions. For safety reasons, treatment should not be continued or resumed with rifampicin.
Because of the ethambutol component, [TB168 trade name] should be used with care in patients with visual
defects. Ocular examinations including acuity, colour discrimination and visual field are recommended
before starting treatment and periodically during treatment, especially if high doses are used. Patients should
be questioned at every visit about their vision and advised to stop taking [TB168 trade name] if a visual
disturbance arises until a clinical evaluation is possible.
[TB168 trade name] is not suitable for use in the treatment of patients with a body weight of less than 25 kg,
since appropriate dose adjustments cannot be made. Other formulations should be used that allow suitable
doses to be given.
Precautions
The precautions for the use of [TB168 trade name] are the same as those that apply for the administration ofrifampicin, isoniazid, pyrazinamide and ethambutol as individual medicinal products.
Patients should be advised against interrupting treatment except as indicated by their health care provider(e.g. pending clinical evaluation if visual disturbances occur).
Impaired liver function, undernourishment, alcoholism
Rifampicin, isoniazid, pyrazinamide and ethambutol are metabolised in the liver. Elevated transaminase
levels, above the upper limit of normal (ULN), commonly occur. Liver dysfunction that may occur in thefirst few weeks of treatment usually returns to the normal range spontaneously, without interruption oftreatment, and usually by the third month of treatment.
With rifampicin, although slight elevations of liver enzymes are common, clinical jaundice or evidence ofhepatitis are rare. In patients taking both isoniazid and rifampicin, a cholestatic pattern with elevated alkaline
phosphatase suggests that rifampicin is the cause, whereas a rise in transaminases may be caused byisoniazid, or rifampicin, or pyrazinamide, or the combination of the three.
Patients with impaired liver function should be treated with caution and under strict medical supervision.
In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase(SGPT/ALAT) and serum glutamic oxaloacetic transaminase (SGOT/ASAT) should be carried out prior totherapy and repeated weekly or fortnightly during therapy. If signs of hepatocellular damage occur, [TB168
trade name] should be withdrawn.
A moderate rise in bilirubin and/or transaminase levels is not in itself an indication for interrupting
treatment; rather, the decision should be made after repeating these liver function tests, noting trends in thelevels, and considering them in conjunction with the patient's clinical condition.
Interrupting isoniazid treatment is recommended when there is clinical jaundice or transaminases exceeding
3 times the ULN. The fixed drug combination, [TB168 trade name], should be replaced by individualcomponent formulations of rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride in order tofacilitate treatment in these clinical circumstances.

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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

Withdrawing rifampicin, pyrazinamide and ethambutol is recommended if liver function does not return tonormal or transaminases exceed 5 times the ULN. The fixed drug combination, [TB168 trade name], should
be replaced by individual component formulations in order to facilitate treatment in these clinicalcircumstances.
Use of isoniazid should be carefully monitored in patients with chronic liver disease. Severe and sometimes
fatal hepatitis caused by isoniazid may occur and may develop even after many months of treatment.
Hepatotoxicity associated with isoniazid therapy (thought to be caused by the metabolite diacetylhydrazine)
is rare in patients up to 20 years of age, but more common with increasing age and affecting up to 3% of
patients aged over 50 years. The incidence of severe hepatotoxicity can be minimised by careful monitoringof liver function. Patients should be monitored for prodromal symptoms of hepatitis, such as fatigue,
weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs of hepatic damage aredetected, treatment should be discontinued promptly. Continued use of [TB168 trade name] in these patients
may cause a more severe form of liver damage.
[TB168 trade name]is not suitable for patients with chronic liver disease, or in chronic alcoholics andundernourished patients, if the dosage of rifampicin, isoniazid, pyrazinamide and ethambutol needs to be
adjusted separately.
For undernourished or elderly patients, supplementation with pyridoxine (vitamin B6) may be useful, because
isoniazid in high doses can lead to pyridoxine deficiency. Pyridoxine supplementation is recommended inmalnourished children and adolescents, in those who are pregnant and those living with HIV, at a dosage of
0.5‒1 mg/kg daily, increased to 2‒5 mg/kg daily if peripheral neuropathy develops.
Impaired renal function
In severe renal insufficiency, the elimination of isoniazid, pyrazinamide and ethambutol can be delayed,leading to a higher systemic exposure and a potential increase in adverse events. [TB168 trade name] should
be used with caution in patients with moderate renal impairment (creatinine clearance 30–60 mL/minute).
Gout
Pyrazinamide and ethambutol should be used with caution in patients with a history of gout. Regularmonitoring of serum uric acid should be undertaken. [TB168 trade name] treatment should be stopped ingouty arthritis.
Haematology
Full blood count should be monitored during prolonged treatment and in patients with hepatic disorders.
Rifampicin should be withdrawn permanently if thrombocytopenia or purpura occur. The possibility ofpyrazinamide having an undesirable effect on blood clotting time or vascular integrity should be borne inmind in patients with haemoptysis.
Diabetes mellitus
Increased difficulty has been reported in controlling diabetes mellitus when such patients are given isoniazid.
Epilepsy
Patients suffering from convulsive disorders must be kept under special observation during treatment with
[TB168 trade name] because of the neurotoxic effects of isoniazid and ethambutol hydrochloride.
Neuropathy
Caution should be exercised in subjects with peripheral or optic neuritis. Regular neurological examination isnecessary, with special care in patients with a history of alcohol abuse. Use of pyridoxine (vitamin B6) may
prevent or diminish neuropathy due to isoniazid treatment especially in elderly and in malnourished patients,
and patients living with HIV. Pyridoxine should be given in line with official guidelines.
Contraception
Additional non-hormonal means of contraception must be employed to prevent the possibility of pregnancy
during treatment with rifampicin (see section 4.5).

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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

Alcohol
Patients should abstain from alcohol while receiving treatment with [TB168 trade name].
Laboratory tests
Full blood counts, liver function tests (SGPT/ALAT, SGOT/ASAT), renal function tests and monitoring
serum uric acid should be performed before treatment and at regular intervals during treatment. Ocularexamination is recommended during treatment with ethambutol hydrochloride.
Concomitant medications
Rifampicin is a potent inducer of the cytochrome P450 system, and may increase the metabolism ofconcomitantly administered drugs resulting in subtherapeutic plasma levels and a lack of effect. Drugs thatare eliminated by hepatic metabolism should only be used concomitantly with [TB168 trade name] if theplasma level or clinical response and undesirable effects can be monitored and the dose can be adequately
adjusted (see section 4.5).
Rifampicin has enzyme inducing properties that can enhance the metabolism of endogenous substrates
including adrenal hormones, thyroid hormones and vitamin D. Isolated reports have associated porphyria
exacerbation with rifampicin administration.
Sodium content
This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially'sodium-free'.
Excipients
This medicinal product contains a colorant (sunset yellow) which may cause allergic reactions.
It is important to consider the contribution of excipients from all the medicines that the patient is taking.
4.5

Interaction with other medicinal products and other forms of interaction

Influence of other medicinal products on [TB168 trade name]
Antacids reduce the bioavailability of rifampicin, isoniazid and ethambutol. To avoid this interaction,[TB168 trade name] should be taken at least 1 hour before antacids. Corticosteroids can reduce the plasma
levels of isoniazid, by increasing its metabolic and/or renal clearance.
Influence of [TB168 trade name] on other medicinal products
Rifampicin is a very potent inducer of the hepatic and intestinal cytochrome P-450 enzyme system(especially the CYP3A and CYP2C subfamilies). Rifampicin is likely to accelerate elimination of coadministered drugs that undergo biotransformation through these metabolic pathways. Rifampicin also
induces UDP-glucuronyltransferase, another enzyme involved in the metabolism of several drugs. This canresult in subtherapeutic plasma levels of co-administered drugs, with a decreased or even a loss of effect.
These effects approach their maximum after about 10 days of treatment, and gradually return to normal in 2
or more weeks after discontinuation. This must be taken into account when co-administering other drugs. To
maintain optimum therapeutic blood levels, doses of drugs metabolised by these enzymes may require
adjustment when starting or stopping the concomitant administration of [TB168 trade name].
In vitro, isoniazid inhibits CYP2C19 and CYP3A4. Thus it may reduce elimination and increase bloodlevels of drugs mainly eliminated through either of these pathways. However, when given with rifampicin, as
when using [TB168 trade name], these effects are likely to be outweighed by the hepatic enzyme induction
due to rifampicin. The net effect on drugs affected in opposite ways by rifampicin and isoniazid (such as
phenytoin, warfarin and theophylline) is hard to predict and may change over time.
Concurrent use of isoniazid with other hepatotoxic or neurotoxic medicines may increase the hepatotoxicity
and neurotoxicity of isoniazid, and should be avoided.
Pyrazinamide may also potentiate the hepatotoxicity of other medicines given concomitantly. Use withprobenecid should preferably be avoided, due to complex pharmacokinetic and pharmacodynamic
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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

interactions that may affect both medicines. Pyrazinamide inhibits urate elimination, and also antagonises theeffect of allopurinol and sulfinpyrazone.
Ethambutol has fewer significant pharmacokinetic or pharmacodynamic interactions with other medicines,
but particular care may be needed if used with other medicines that also affect visual function.
Thus, mainly due to rifampicin, [TB168 trade name] may interact with a very large number of other drugs,
primarily by reducing the exposure to co-administered agents, reducing their efficacy and increasing the riskof therapeutic failure. For many important medicines, no interaction data with rifampicin are available.
However, clinically significant reductions in drug exposure may occur.
Whenever co-prescribing any drug together with [TB168 trade name], the possibility of a drug-druginteraction should be considered. The following list of drug interactions with [TB168 trade name] is not
exhaustive, but is a selection of interactions of putative importance. The scope of the table is largely based on
the WHO Essential Medicines List.
Drugs

Recommendations on coadministration

Interaction

INFECTION
Antiretrovirals
Nucleoside analogues
Zidovudine / rifampicin

Zidovudine AUC  47%

The clinical significance of thelowered zidovudine exposure is
unknown. Dose modifications ofzidovudine in this situation have notbeen formally evaluated.

Didanosine
Emtricitabine
Lamivudine
Stavudine

No interaction expected

No dose adjustment required.

Tenofovir alafenamide/
emtricitabine/
rifampicin

Interaction not studied. Coadministration of rifampicin, a
P-gp inducer, may decrease
tenofovir alafenamide plasma
concentrations, which may
result in loss of therapeutic
effect and development ofresistance.

Co-administration is notrecommended.

Tenofovir disoproxil / rifampicin

Tenofovir AUC  13%

No dose adjustment required.

Abacavir / rifampicin

Empirical data are lacking, butrifampicin may decreaseabacavir exposure throughinduction of glucuronidation.

Efficacy of abacavir should beclosely monitored in co-treatment.

Non-nucleoside analogues
Efavirenz / rifampicin

Efavirenz AUC  26%

Nevirapine / rifampicin

Nevirapine: AUC  58%

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When co-treating with [TB168 tradename], increasing the efavirenz doseto 800 mg daily may be considered
Concomitant use of [TB168 tradename] and nevirapine is notrecommended since appropriate
doses of nevirapine when given
concomitantly with rifampicin havenot been established and the safetyof the combination is unknown,

Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

Drugs

Interaction

Recommendations on coadministration

Etravirine / rifampicin

Rifampicin is likely tosignificantly reduce exposure
to etravirine.

Co-treatment of [TB168 trade name]and etravirine should be avoided.

Protease inhibitors
Atazanavir / rifampicin
Boceprevir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Ritonavir
Saquinavir
Tipranavir

Protease inhibitors exposure
will be reduced tosubtherapeutic level due tointeraction with rifampicin.
Increasing doses, or an increasein ritonavir-boosting, havebeen ineffective or ill-tolerated
with a high rate ofhepatotoxicity.

[TB168 trade name] must not be coadministered with proteaseinhibitors for treating HIV or
hepatitis C virus infections (seesection 4.3).

Co-treatment should be avoided. If
deemed necessary, consider
increasing the raltegravir dose to
600 mg twice daily

OthersRaltegravir / rifampicin

Raltegravir AUC ↓ 40%

Dolutegravir / rifampicin

Dolutegravir AUC ↓ 54%

A dose adjustment of dolutegravir to
50 mg twice daily is recommended
when co-administered with [TB168
trade name] in the absence ofintegrase class resistance. In thepresence of integrase classresistance this combination should
be avoided.

Elvitegravir/cobicistat/rifampicin

Co-administration has not beenstudied. Rifampicin is a potent
inducer of CYP450
metabolism and may causesignificant decrease in theplasma concentration ofelvitegravir and cobicistat
resulting in loss of therapeutic
effect.

Co-administration iscontraindicated.

Maraviroc / rifampicin

Maraviroc AUC ↓ 63%

Co-treatment should be avoided. If
deemed necessary, the maraviroc
dose should be increased to 600 mg
twice daily.

Rifampicin:
Co-administration has notbeen studied but is expected
to decrease concentrations ofthese hepatitis C virus
antivirals due to induction of
CYP3A4 by rifampicin andhence to reduce their
therapeutic effect.

Co-administration of [TB168 tradename] with these antivirals is
contraindicated (for further details
see summary of productcharacteristics of antivirals fortreating hepatitis C virus infection).

Antivirals for hepatitis C infection
Daclatasvir
Elbasvir/Grazoprevir
Glecaprevir/Pibrentasvir
Ledipasvir/Sofosbuvir
Ombitasvir/paritaprevir/ritonavir(with or without dasabuvir)
Simeprevir
Sofosbuvir (with or without
velpatasvir with or without
voxilaprevir) /Isoniazid:
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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

WHOPAR Part 4

March 2023

Recommendations on coadministration

Drugs

Interaction

Rifampicin
Isoniazid

Co-administration has notbeen studied. Patients withcurrent chronic liver disease
should be carefully
monitored. Severe andsometimes fatal hepatitis
associated with isoniazid may
develop even after many
months of treatment.

Antifungals
Ketoconazole / rifampicin

Ketoconazole AUC  80%

Co-administration should be
avoided. If deemed necessary, adose increase of ketoconazole may
be required.

Fluconazole / rifampicin

Fluconazole AUC ↓ 23%

Monitor therapeutic effect. An
increased dose of fluconazole may
be required.

Itraconazole / rifampicin

Itraconazole AUC ↓ 64–88%

Co-administration should be
avoided.

Voriconazole / rifampicin

Voriconazole AUC ↓ 96%

Co-administration iscontraindicated. If necessary,rifabutin should be substituted forrifampicin.

Clarithromycin / rifampicin

Clarithromycin mean serum
concentration ↓ 85%. 14-OH
clarithromycin levels
unchanged.

Co-administration should be
avoided.

Chloramphenicol / rifampicin

Case reports indicate 60–80%
reduction of chloramphenicol
exposure.

Co-administration should be
avoided.

Ciprofloxacin / rifampicin

No significant interaction

No dose adjustment required.

Doxycycline / rifampicin

Doxycycline AUC ↓ 50–60%

If co-treatment is considerednecessary, the dose of doxycycline
should be doubled.

Metronidazole / rifampicin

Metronidazole AUC i.v.↓ 33%

The clinical relevance of theinteraction is unknown. Doseadjustment is not routinely
recommended. Efficacy should bemonitored.

Sulfamethoxazole / rifampicin

Sulfamethoxazole AUC  23%

Interaction probably not clinicallysignificant. Efficacy ofsulfamethoxazole should bemonitored.

Trimethoprim / rifampicin

Trimethoprim AUC  47%

A dose increase of trimethoprim
may be required. Efficacy should bemonitored.

Antibacterials/tuberculosis medicines

Rifampicin and ethionamide should
not be co-administered, due to anincreased risk of hepatotoxicity.

Ethionamide / rifampicin

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Rifampicin/Isoniazid/Pyrazinamide/Ethambutol
150mg/75mg/400mg/275mg film-coated tablets(Macleods Pharmaceuticals Ltd), TB168

Drugs

WHOPAR Part 4

March 2023

Recommendations on coadministration

Interaction

Antimalarials
Empirical data are not available.
Since chloroquine undergoes
polymorphic hepatic metabolism,
lower levels are likely during
rifampicin co-therapy. Coadministration should be avoided.

Chloroquine / rifampicin

Atovaquone / rifampicin

Atovaquone AUC ↓ 50%
Rifampicin AUC ↑ 30%

Co-administration should be
avoided.

Mefloquine / rifampicin

Mefloquine AUC ↓ 68%

Co-administration should be
avoided.

Amodiaquine / rifampicin

Empirical data are notavailable. Since amodiaquine
undergoes hepatic metabolism,
it is likely that clearance isincreased when co-treatingwith rifampicin.

Co-administration should be
avoided.

Quinine / rifampicin

Quinine AUC ↓  80%.
This has been associated withsignificantly higher
recrudescence rates.

Co-administration should be
avoided. If co-administration isdeemed necessary, an increased doseof quinine should be considered.

Lumefantrine / rifampicin

Lumefantrine AUC ↓ 68%

Co-administration should be
avoided.

Artemisinin and its derivatives /rifampicin

Artemether AUC ↓ 89%
Dihydroarthemisinin AUC ↓85%

Co-administration should be
avoided.

ANALGESICS, ANTIPYRETICS, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Morphine / rifampicin

Morphine AUC p.o  30%,
loss of analgesic effect.

Co-treatment should be avoided. If
deemed necessary, efficacy should
be monitored and the dose may need
to be increased.

Codeine / rifampicin

Plasma levels of morphine, theactive metabolite of codeine,are likely to be substantiallyreduced.

Efficacy should be monitored andcodeine dose increased if necessary.

Paracetamol (acetaminophen)/ rifampicin

Rifampicin may increase theglucuronidation of paracetamoland decrease its efficacy.
There may be an increased riskof hepatotoxicity on coadministration, but data areinconclusive. Concurrent use
with isoniazid may increase
hepatotoxicity.

Co-administration of [TB168 tradename] and paracetamol should be
avoided.

Rifampicin has been reported
to produce a 65% decrease in
etoricoxib plasma
concentrations when given
concomitantly.

Patients should be monitored forpossible loss of analgesic effect;
however, evidence to support anincrease in analgesic dose is lacking.

/ isoniazid

Etoricoxib / rifampicin

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WHOPAR Part 4

March 2023

Interaction

Recommendations on coadministration

Carbamazepine / rifampicin/ isoniazid

Rifampicin is expected todecrease serum concentrationsof carbamazepine whereas
isoniazid may increase them.
Neurological side effects andthe risk of hepatotoxicity
increase when co-treating withcarbamazepine.

Co-administration of [TB168 tradename] and carbamazepine should be
avoided.

Phenobarbital / rifampicin/ isoniazid

Phenobarbital and rifampicin
are both strong hepatic enzyme
inducers, and each may lower
the plasma concentrations of
the other. Also, co-treatment
with phenobarbital andisoniazid may increase the riskof hepatotoxicity.

Co-administration of [TB168 tradename] and phenobarbital should beundertaken with caution, and thepatient monitored for clinical effects
and, if possible, plasma drugconcentrations.

Phenytoin / rifampicin
isoniazid

Phenytoin AUC i.v.  42%
Co-treatment with phenytoin
and isoniazid may result in an
increased risk ofhepatotoxicity.

Co-treatment with phenytoin and[TB168 trade name] should be
avoided.

Valproic acid / rifampicin

Interaction studies are lacking.
Since valproic acid iseliminated through hepatic
metabolism, including
glucuronidation, reduced
plasma levels of valproic acidare likely with concomitantuse.

Co-treatment should be avoided. If
deemed necessary, efficacy and, if
possible, also plasma concentrationsof valproic acid, should be carefully
monitored.

Lamotrigine / rifampicin

Lamotrigine AUC  45%

Co-treatment should be avoided. If
deemed necessary, lamotrigine doseshould be increased as appropriate.

Ciclosporin / rifampicin

Several studies and case reports
have shown substantially
increased ciclosporin clearance
when co-administered withrifampicin.

Co-administration should be
avoided. If deemed necessary,
plasma concentrations of ciclosporin
should be monitored and doses
adapted accordingly (3- to 5-foldincreases in ciclosporin dose havebeen required).

Tacrolimus / rifampicin
Sirolimus
Everolimus

Tacrolimus AUC i.v. ↓ 35%;
AUC p.o ↓ 6870%
Sirolimus AUC ↓82%
Everolimus AUC ↓ 63%

Co-administration of [TB168 tradename] and mTOR inhibitors should
be avoided. If deemed necessary,
plasma drug concentrations should
be monitored, and the dose
increased as appropriate.

No interaction expected

No dose adjustment required.

Drugs
ANTIEPILEPTICSIMMUNOSUPPRESSANTS

CARDIOVASCULAR MEDICINES
ACE inhibitors
Enalapril / rifampicin

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WHOPAR Part 4

March 2023

Interaction

Recommendations on coadministration

Lidocaine / rifampicin

Lidocaine CLi.v. ↑ 15%

No dose adjustment required

Verapamil / rifampicin

S-verapamil p.o CL/F ↑ 32fold. With i.v. S-verapamil, CL↑ 1.3-fold[TB168 trade name] and oral formsof verapamil should not be coadministered. If i.v. verapamil isgiven, the therapeutic effect should
be carefully monitored; dose
adjustment may be required.

Warfarin AUC ↓ 85%
Isoniazid may inhibit hepatic
metabolism of warfarin.

Monitor closely and adjust warfarindose as needed and reduce dose after
withdrawing rifampicin treatment.

Atenolol AUC ↓ 19%

No dose adjustment required.

Amlodipine is metabolised by
CYP3A; lower exposure of
amlodipine and potentiallyother calcium- channel
blockers is expected when cotreating with rifampicin.

Efficacy should be monitored.

AUC p.o ↓ 30%

When co-administering [TB168
trade name] with digoxin, theefficacy and plasma concentration ofdigoxin should be monitored. A
dose increase may be required.

Simvastatin / rifampicin

Simvastatin AUC ↓ 87%
Simvastatin acid AUC ↓ 93%

Co-administration is notrecommended.

Atorvastatin / rifampicin

Atorvastatin AUC ↓ 80%

Co-administration is notrecommended

Drugs
Antiarrhythmics

Anticoagulants
Warfarin and other coumarin
anticoagulants / rifampicin/isoniazid
Beta blockers
Atenolol / rifampicin
Calcium-channel blockers
Amlodipine / rifampicin

Cardiac glycosides
Digoxin / rifampicin

Statins

GASTROINTESTINAL MEDICINES
Ranitidine / rifampicin

Ranitidine AUC ↓ 52%

Page 12 of 28

Efficacy should be monitored, andranitidine dose increased if
necessary.

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Drugs

Interaction

Recommendations on coadministration

Antacids / isoniazid/ rifampicin

Antacids may reduce thebioavailability of rifampicin,
isoniazid and ethambutol, in
the former case by up to athird.

Acid-suppressing drugs or antacids
that do not contain aluminiumhydroxide should be used if cotreatment with [TB168 trade name]is necessary.
[TB168 trade name] should be taken
at least 1 hour before the antacid.

Aluminium hydroxide impairs
the absorption of isoniazid.

PSYCHOTHERAPEUTIC MEDICINES
Anxiolytics and hypnotics
Diazepam / rifampicin/ isoniazid
Midazolam
Triazolam
Alprazolam
Nitrazepam

Diazepam AUC  > 70%
Midazolam AUC  98%
Triazolam AUC  95%
Alprazolam AUC  88%
Reduced nitrazepam throughconcentrations, increased
clearance.

Co-treatment is not recommended.
Benzodiazepine withdrawal may
occur in dependent individuals.

Zolpidem / rifampicin
Zopiclone / rifampicin

Zolpidem AUC 73%
Zopiclone AUC 82%

Co-administration should be
avoided.

Chlorpromazine / rifampicin/ isoniazid

Rifampicin may reduce
chlorpromazine exposure.
Also, concomitant use ofchlorpromazine with isoniazid
may impair the metabolism of
isoniazid.

Co-administration should be
avoided. If considered necessary,patients should be carefully
monitored for isoniazid toxicity.

Haloperidol / rifampicin
Clozapine

Haloperidol clearance issubstantially increased byrifampicin; theoreticalconsiderations imply that same
applies to clozapine.

If co-treatment of [TB168 tradename] with haloperidol or clozapine
is deemed necessary, monitor
clinical efficacy. A dose increase
may be required.

Case reports (supported bytheoretical considerations)suggest that rifampicin
considerably increases
clearance of tricyclic
antidepressants.

Co-treatment should be avoided. If
necessary, monitor for clinicalresponse, side effects, and, if
possible, plasma concentrations.

Antipsychotics

Tricyclic antidepressants
Amitriptyline / rifampicin
Nortriptyline

HORMONES; OTHER ENDOCRINE MEDICINES AND CONTRACEPTIVES
Corticosteroids
Prednisolone
Other systemically administeredcorticosteroids /rifampicin

Prednisolone AUC ↓ 66%
Also for other corticosteroids,
exposure is likely to be
substantially decreased whenco-treating with rifampicin.
Page 13 of 28

Co-administration of [TB168 tradename] with corticosteroids should be
avoided. If deemed necessary, theclinical status of the patient should
be carefully monitored, andcorticosteroid doses adjusted asneeded.

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Interaction

Recommendations on coadministration

Glibenclamide / rifampicin
Glimepiride
Repaglinide

Glibenclamide AUC ↓ 39%
Glimepiride AUC ↓ 34%
Repaglinide AUC ↓ 57%

Blood glucose levels should beclosely monitored. A dose increaseof diabetes medication may berequired.

Insulin

No interaction expected.

No dose adjustment required.

Case reports indicate thatrifampicin may decrease theeffect of levothyroxine.

TSH levels should be monitored.

Ethinylestradiol / rifampicin

Ethinylestradiol AUC ↓ 66%

Co-administration with [TB168
trade name] may be associated withdecreased contraceptive efficacy.
Barrier or other non-hormonal
methods of contraception should be
used.

Norethisterone (norethindrone) /rifampicin

Norethisterone AUC ↓ 51%

Co-administration with [TB168
trade name] may be associated withdecreased contraceptive efficacy.
Barrier or other non-hormonal
methods of contraception should be
used.

Disulfiram / isoniazid

Concurrent use of disulfiram
together with isoniazid may
increase incidence of adverse
effects on the central nervous
system.

Dose reduction or discontinuation ofdisulfiram may be necessary during
therapy with [TB168 trade name].

Enflurane / isoniazid

Isoniazid may increase theformation of the potentiallynephrotoxic inorganic fluoride
metabolite of enflurane.

Co-administration of [TB168 tradename] with enflurane should be
avoided.

Methadone / rifampicin

Methadone AUC ↓ 33-66%

Patients should be monitored forpossible withdrawal effects, andmethadone dose increased as
appropriate (up to 2-3 fold)..

Praziquantel / rifampicin

Praziquantel AUC  80-99%

Co-treatment with [TB168 tradename] should be avoided.

Theophylline / isoniazid/ rifampicin

Isoniazid may increase theserum concentration oftheophylline and rifampicin
may increase it. The effects ofcombination are unknown.

Theophylline dose adjustment may
be needed.

Typhoid vaccine, oral /pyrazinamide

Antibiotics may inactivate oral
typhoid vaccine

Avoid concomitant administration
oral typhoid vaccine with [TB168
trade name]

Drugs
Antidiabetics

Thyroid hormones
Levothyroxine / rifampicin

Hormonal contraceptives

OTHERS

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Interactions with foodIsoniazid is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO), which can reducetyramine and histamine metabolism, causing symptoms such as headache, sweating, palpitations, flushing,and hypotension. Patients should therefore be advised against ingesting foods rich in tyramine and/or
histamine, such as cured meat, some cheeses (e.g. matured cheeses), wine, beer and some fish (e.g. tuna,mackerel, salmon).
Interactions with diagnostic tests
Rifampicin can delay the biliary excretion of contrast media during gallbladder radiographic examination.
Microbiological methods used to determinate folic acid and cyanocobalamin (vitamin B12) plasma
concentrations cannot be used during rifampicin treatment as rifampicin is in competition with bilirubin and
BSP. To avoid false positive reactions, BSP test should be carried out the morning before rifampicin
administration.
4.6

Fertility, pregnancy and breastfeeding

Pregnancy
There are no or limited amount of data from the use of rifampicin in pregnant women. Studies on rifampicinin animals have shown reproductive toxicity (see section 5.3).
No adverse effects of isoniazid, ethambutol or pyrazinamide on the fetus have been reported. Use ofrifampicin in the third trimester has been associated with postnatal haemorrhages in the mother and infant.
[TB168 trade name] can be used in pregnancy if the benefits are considered to outweigh the risks. The
treatment of TB in pregnant women is the same as for non-pregnant women. As maternal TB increases therisk of vertical transmission of HIV, TB treatment must be started promptly to prevent transmission.
If [TB168 trade name] is used in the last weeks of pregnancy, the mother and neonate should receive vitamin
K.
Supplemental pyridoxine (vitamin B6) may be advised in pregnant adolescents (see section 4.4)..
Breastfeeding
Rifampicin, isoniazid, pyrazinamide and ethambutol appear in human milk. However, concentrations inbreast milk are so low that breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis ortherapy for nursing infants. No effects on the breastfed newborns/infants are anticipated.
[TB168 trade name] can be used during breast-feeding.
Fertility
No human data on the effect of [TB168 trade name] on fertility are available. Animal studies indicate thatco-administration of ethambutol, rifampicin, isoniazid, and pyrazinamide has effects on fertility (see section
5.3).
4.7

Effects on ability to drive and use machines[TB168 trade name] has minor to moderate influence on the ability to drive and use machines.
The clinical status of the patient and the adverse reaction profile of [TB168 trade name] should be borne inmind when considering the patient’s ability to drive or operate machinery. In particular, undesirable effectsof ethambutol, such as confusion, disorientation, hallucinations, dizziness, malaise and visual disturbances(blurred vision, red-green colour blindness, loss of vision), and neurotoxicity associated with isoniazid, may
impair the patient's ability to drive or operate machinery.

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4.8

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Undesirable effects

The most important adverse reactions of [TB168 trade name] are hepatotoxicity, neurotoxicity and effects on
vision, due to the components of the fixed-dose combination.
The most important adverse reactions caused by rifampicin are hepatotoxicity, particularly cholestatic
reactions, and skin reactions. Rifampicin may cause subclinical, unconjugated hyperbilirubinaemia or
jaundice without hepatocellular damage, but occasionally causes hepatocellular injury. It can also potentiate
the hepatotoxicity of the other anti-tuberculosis medications.
The most important adverse reactions of isoniazid are peripheral and central neurotoxic effects, andhepatotoxicity. Severe and sometimes fatal hepatitis due to isoniazid therapy has been reported. The majorityof cases have occurred within the first three months of therapy, but hepatotoxicity may also develop after alonger duration of treatment.
The most important adverse effect of pyrazinamide is liver damage, ranging from asymptomatic increases ofserum transaminases to symptomatic liver dysfunction, and in rare cases also fatal liver failure.
The most important adverse reaction of ethambutol is retrobulbar neuritis with reduced visual acuity.
Tabulated list of adverse reactions
In the tables below, ADRs are listed under system organ class (SOC) and ranked by headings of frequency.
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness,using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000
to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), not known (cannot be estimated from theavailable data). The table in this section is for adult patients only. Tables have been included for each of thecomponents of the fixed dose combination
Undesirable effects of rifampicin daily therapy
Nervous system disorders
CommonTiredness, drowsiness, headache, light-headedness, dizzinessRare

Ataxia, muscular weakness, myopathy

Psychiatric disorders
Rare

Mental confusion, psychosis

Gastrointestinal disorders
CommonAnorexia, nausea, abdominal pain, bloatedness

Rare

Vomiting, diarrhoea, isolated occurrences of erosive gastritis and pseudomembranous colitis,
pancreatitis

Hepatobiliary disorders
CommonAsymptomatic increase in liver enzymes

Rare

Hepatitis or jaundice, induction of porphyria

Renal and urinary disorders
Rare

Elevations of blood urea nitrogen and serum uric acid. Acute renal failure due to haemoglobinuria,
haematuria, interstitial nephritis, glomerulonephritis and tubular necrosis have been reported.

Endocrine disorders
Not known

Adrenal insufficiency, induction of crisis in Addison patients

Metabolism and nutritional disorders
Unknown

Decreased appetite

General disorders
Very common

Pyrexia, chills

CommonReddish discoloration of body fluids and secretions such as e.g. urine, sputum, lacrimal fluid,
faeces, saliva and sweat; paradoxical drug reaction (appearance of new tuberculosis symptoms
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despite adherence and absence of resistance).
Not known

Collapse, shock, oedema

Blood and lymphatic system disorders
Rare

Transient leucopenia, eosinophilia, agranulocytosis.
Thrombocytopenia and thrombocytopenic purpura occur more frequently with intermittent therapy
than with continuous daily treatment, during which they occur only very rarely. When rifampicin
administration has been continued after the occurrence of purpura, cerebral haemorrhage andfatalities have been reported.
Haemolysis, haemolytic anaemia

Not known

Disseminated intravascular coagulation has also been reported.

Skin and subcutaneous tissue disorders
CommonFlushing, itching with or without skin rash, urticaria

Rare

Severe skin reactions such as Stevens-Johnson syndrome and generalised hypersensitivity reactions,e.g. exfoliative dermatitis, Lyell syndrome and pemphigoid reactions

Immune System Disorders
Not known

Anaphylaxis

Musculoskeletal disorders
Not known

Muscle weakness, myopathy, bone pain

Eye disorders
CommonReddening of the eyes, permanent discoloration of soft contact lenses

Rare

Visual disturbances, exudative conjunctivitis

Reproductive system and breast disorders
Rare

Menstrual disturbances (in extreme cases, amenorrhoea);

Vascular disorders
Not known

Shock, flushing, vasculitis, bleeding

Investigations
CommonBlood bilirubin increased, aspartate aminotransferase increased, alanine aminotransferase increased[TB168 trade name] should not be used for intermittent treatment regimens. In patients taking rifampicin
other than on a daily basis or in those resuming treatment after a temporary interruption, an influenza-like
syndrome may occur, this being very probably of immunopathological origin. It is characterised by fever,shivering and possibly headache, dizziness and musculoskeletal pain. In rare cases this flu-like syndrome
may be followed by thrombocytopenia, purpura, dyspnoea, asthma-like attacks, haemolytic anaemia, shock
and acute renal failure. These serious complications may, however, also set in suddenly without preceding
flu-like syndrome, mainly when treatment is resumed after a temporary interruption or when rifampicin isgiven only once a week in high doses (≥ 25 mg/kg). When rifampicin is given in lower doses (600 mg) 2–3
times a week, the syndrome is less common, the incidence then being comparable to that observed during
daily medication.
Undesirable effects of isoniazid
Nervous system disorders
Very common

Peripheral neuropathy, usually preceded by paraesthesia of the feet and hands. The frequency
depends on the dose and on predisposing conditions such as malnutrition, alcoholism or diabetes.
It has been reported in 3.5 to 17% of patients treated with isoniazid. Concomitant pyridoxine
administration largely reduces this risk (see section 4.4).

UncommonSeizures, toxic encephalopathy

Not known

Polyneuritis, presenting as muscle weakness, loss of tendon reflexes
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Hyperreflexia may be troublesome with doses of 10 mg/kg
Psychiatric disorders
Uncommon

Memory impairment, toxic psychosis

Not known

Elevated mood, psychotic disorder
Although isoniazid usually has a mood-elevating effect, mental disturbances, ranging from minor
personality changes to major mental derangement have been reported; these are usually reversed onwithdrawal of the drug

Gastrointestinal disorders
Not known

nausea, vomiting, anorexia, dry mouth, epigastric distress, constipation, pancreatitis
acute

Hepatobiliary disorders
Very common

Transient elevation of serum transaminases

UncommonHepatitis

Not known

Acute hepatic failure, liver injury, jaundice
The risk of these undesirable effects increases with age, especially over the age of 35; it may beserious and sometimes fatal with the development of necrosis.

Renal and urinary disorders
Not known

Dysuria

Metabolic and nutritional disorders
Not knownHyperglycaemia, metabolic acidosis, pellagra, pyridoxine deficiency, nicotinic acid deficiency
Nicotinic acid deficiency may be related to isoniazid-induced pyridoxine deficiency which affects
the conversion of tryptophan to nicotinic acid.

General disorders
Not known

Pyrexia

Respiratory, thoracic and mediastinal disorders
Not known

Pneumonitis (allergic), interstitial lung disease

Blood and lymphatic system disorders
Not known

Anaemia (haemolytic, sideroblastic, or aplastic), thrombocytopenia, leucopenia (allergic),
neutropenia with eosinophilia, agranulocytosis, lymphadenopathy

Skin and subcutaneous tissue disorders
Rare

Toxic epidermal necrolysis, eosinophilia systemic symptoms

Not known

Erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, pemphigus, rash, acne

Immune System Disorders
Not known

Anaphylactic reactions

Musculoskeletal disorders
Not known

Arthritis, systemic lupus erythematosus, lupus-like syndrome, rheumatic syndrome

Eye disorders
UncommonOptic atrophy or neuritis

Ear and labyrinth disorders
Not known

Deafness, tinnitus, vertigo
These have been reported in patients with end-stage renal impairment

Reproductive system and breast disorders
Not known

Gynaecomastia

Vascular disorders
Not known

Vasculitis
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Investigations
Not known

Anti-nuclear bodies

Miscellaneous
Withdrawal symptoms, which may occur on cessation of treatment, include headache, insomnia, excessive dreaming,
irritability and nervousness.

Undesirable effects of pyrazinamide
Nervous system disorders
Not known

Headache, dizziness, nervousness, insomnia

Gastrointestinal disorders
CommonNausea, vomiting

Not known

Abdominal cramps, anorexia

Hepatobiliary disorders
Very common

Increased liver enzymes

UncommonJaundice

Rare

Liver failure

Metabolism and nutrition disorders
Very common

Hyperuricaemia

Very rare

Pellagra, aggravated porphyria

Renal and urinary disorders
Not known

Interstitial nephritis

Skin and subcutaneous tissue disorders
Rare

Rash, photosensitivity reaction, urticaria

General disorders
Very common

Flushing

Not known

Malaise, fever, weight loss, allergic reactions

Blood and lymphatic systems disorders
Not known

Anaemia, thrombocytopenia, neutropenia

Musculoskeletal disorders
Very common

Arthralgia

Unknown

Gouty arthritis

Vascular disorders
Not knownHypertension

Undesirable effects of ethambutol
Nervous system disorders
Rare

Peripheral neuritis, peripheral neuropathy, paraesthesia (especially in the extremities), numbness

Very rare

Disorientation, dizziness, headache

Psychiatric disorders
Very rare

Mental confusion and hallucination
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Gastrointestinal disorders
Not known

Nausea, vomiting, anorexia, flatulence, abdominal pain, diarrhoea

Hepatobiliary disorders
Very rare

Hepatic failure

Not known

Hepatitis, jaundice, increase in liver enzymes

Renal and urinary disorders
Very rare

Nephrotoxicity including interstitial nephritis

Eye disorders
UncommonOptic neuritis (decreased visual acuity, loss of vision, scotoma, colour blindness, visual
disturbance, visual field defect, eye pain)

Blood and lymphatic systems disorders
Rare

Thrombocytopenia,

Very rare

Leucopenia, neutropenia

Respiratory, thoracic and mediastinal disorders
Very rare

Pneumonitis, pulmonary infiltrates, with or without eosinophilia

Metabolism and nutrition disorders
UncommonHyperuricaemia

Very rare

Gout

Immune system disorders
Very rare

Hypersensitivity, anaphylactoid reactions (see also “Skin and subcutaneous tissue disorders”)

Skin and subcutaneous tissue disorders
Rare

Rash, pruritus, urticaria

Very rare

Photosensitive lichenoid eruptions, bullous dermatitis, Stevens-Johnson syndrome, epidermal
necrolysis

Musculoskeletal and connective tissue disorders
Very rare

Joint pains

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

Rifampicin
Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within ashort time after acute ingestion; unconsciousness may occur when there is severe hepatic disease. Transient
increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange colouration of the skin, urine,
sweat, saliva, tears and faeces will occur, and its intensity is proportional to the amount ingested. Facial or
periorbital oedema has also been reported in children. Hypotension, sinus tachycardia, ventriculararrhythmias, seizures and cardiac arrest were reported in some fatal cases.
The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults
have been reported with doses ranging from 9 to 12 g rifampicin. Fatal acute overdoses in adults have beenreported with doses ranging from 14 to 60 g. Alcohol or a history of alcohol abuse was involved in some of
the fatal and nonfatal reports.
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Nonfatal overdoses in paediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses have beenreported.
Management
Intensive supportive measures should be instituted and individual symptoms treated as they arise. The
instillation of activated charcoal slurry into the stomach shortly after overdose may help absorb any
remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe
nausea and vomiting. Active diuresis (with measured intake and output) will help promote excretion of the
drug. Haemodialysis may be of value in some patients
Isoniazid
Typical symptoms are seizures and metabolic acidosis, ketonuria, hyperglycaemia. In addition, there may beperiorbital myoclonus, dizziness, tinnitus, tremor, hyperreflexia, paraesthesia, hallucinations, impaired
consciousness, respiratory depression, apnoea, tachycardia, arrhythmias, hypotension, nausea, vomiting.
fever, rhabdomyolysis, disseminated intravascular coagulation, hyperglycaemia, hyperkalaemia and lLiverinvolvement.
Doses of isoniazid exceeding 10 mg/kg may adversely affect the nervous system, e.g. in the form of
peripheral neuropathy, and thus impair the patient’s ability to drive or operate machinery.
Isoniazid toxicity is potentiated by alcohol. Lethal dose is thought to be 80–150 mg/kg bodyweight.
Administration of 3 g to a 5-year old and 5‒7.5 g to adults resulted in extremely severe intoxication. A 5-gdose in a 15-year old resulted in lethal intoxication. A dose of 900 mg in an 8-year old has resulted inmoderate intoxication and 2–3 g to a 3-year old resulted in severe intoxication.
Management
Where considered appropriate, evacuation of the stomach (provided the patient is not experiencing seizures)
and administration of activated charcoal can reduce absorption if instituted within a few hours of ingestion.
Blood samples must be collected for immediate determination of blood gases, electrolytes, BUN, glucose
etc. Subsequently, pyridoxine is given (intravenous bolus on a gram-per-gram basis, equal to the isoniazid
dose; if the isoniazid dose is unknown an initial dose of 5 g in adults or 80 mg/kg in children should beconsidered),Pyridoxine should be diluted to reduce vascular irritation and is administered for 30 minutes via
infusion pump or syringe pump. The dose is repeated if necessary.
Intravenous diazepam (in case of seizures not responding to pyridoxine) and haemodialysis may be of value.
Further treatment should be supportive, with special attention to monitoring and support of ventilation andcorrection of metabolic acidosis. There is no specific antidote.
Pyrazinamide
Abnormal liver function tests, hyperuricaemia.
Ethambutol
Loss of appetite, gastro-intestinal disturbances, fever, headache, dizziness, confusion, hallucinations.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of drugs for treatment of tuberculosis (rifampicin, pyrazinamide,ethambutol and isoniazid).
ATC code: J04A M06.
Rifampicin is a rifamycin antibiotic. Isoniazid, pyrazinamide and ethambutol are bactericidal antituberculous
agents.
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Mechanism of action
Rifampicin exerts, both in vitro and in vivo bactericidal effects on Mycobacterium tuberculosis. It also
exhibits variable activity against other atypical species of Mycobacterium.
In vivo rifampicin exerts its antibacterial effect not only on micro-organisms in the extracellular spaces but
also on those located intracellularly.
Rifampicin inhibits the DNA-dependent RNA polymerase of sensitive bacterial strains, but without affecting
the host enzymatic systems.
Isoniazid exerts a bactericidal effect mainly on rapidly growing populations of Mycobacterium tuberculosis.
Its mechanism of action is probably based chiefly on inhibition of mycolic acid synthesis, mycolic acids
being important constituents of the mycobacterial cell wall.
Pyrazinamide: The exact mechanism of action is unknown. In vitro and in vivo studies have demonstrated
that pyrazinamide is only active at a slightly acidic pH (pH 5.5).
Ethambutol: The mechanism of action is not fully known. It diffuses into mycobacteria and appears tosuppress multiplication by interfering with RNA synthesis. It is effective only against mycobacteria that are
actively dividing.
5.2

Pharmacokinetic properties

The absorption characteristics of [TB168 trade name] have been determined after administration of 1 tablet
in healthy volunteers in the fasting state as follows:
Pharmacokinetic variable

Maximum concentration(Cmax)µg/ml
Area under the curve(AUC0–t), a measure of theextent of absorptionµg.hour/ml
Time to attain maximum
concentration (tmax) hour

Mean value ± standard deviation
Ethambutol

Isoniazid

Pyrazinamide

Rifampicin

3.27 ± 1.09

5.69 ± 1.56

31.40 ± 2.55

9.83 ± 1.70

19.34 ± 3.35

32.26 ± 15.19

515.4 ± 61.8

65.07 ± 13.35

3.02 ± 0.58

1.37 ± 0.62

1.98 ± 0.63

1.92 ± 0.62

Pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol

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Rifampicin

WHOPAR Part 4

Isoniazid

March 2023

Pyrazinamide

Ethambutol

Absorption
Absolutebioavailability

90 ̶ 95%

Oral
bioavailability> 90%

Food effect

> 90%

NA*

NA*

> 80%

NA*

70–80%

Reduced.

None

None

43 L

40 L

20 L

60 ̶ 90%< 10%

10–20%

10–40%

CSF concentrations areof the same order ofmagnitude as theunbound concentrations
in plasma.

Diffuses readily
into all body fluids(cerebrospinal,
pleural and ascitic
fluids), tissues,organs and excreta(saliva, sputum
and faeces).
Crosses theplacenta andpasses into milk.

Widely distributed into
body tissues and fluids
including the liver,lungs, and CSF.
In CSF concentrations
are approximately
equal to plasma
concentrations.

CSF: Relatively low
concentrations
distributed to CSF

No effect on extent ofabsorption. Rate ofabsorption is reduced.

Distribution
Volume of
distribution(mean)
Plasma protein
binding in vitro
Tissue distribution

55 L

Concentrations in liver,spleen, kidneys andlung tissue are higher
than serum
concentrations.
Penetrates into vaginal
and cervical tissue andinto cervicovaginal
fluid.
Passes into theplacenta; serum
concentration in fetus isabout ⅓ of those inmother.
Metabolism
Primarily hepatic,
rapidly deacetylated.
Activemetabolite(s)25-o-deacetyl
rifampicin

Hepatic; primarily
acetylated by Nacetyltransferase
to Nacetylisoniazid
Nicotinoyl-NAD
adductHepatic
Hepatic

Pyrazinoic acidNA*

9 ̶ 10 hours

3–4 hours

Elimination
Elimination halflife

3 ̶ 5 hours
Decreases to 2 ̶ 3 hours
after repeated

1.2 hours: rapid
acetylators
3.5 hours: Slow
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administration
Mean systemic
clearance (Cl/F)
5.7 ̶ 9.0 L/hour% of dose excreted
in urine30%% of dose excreted
in faeces60 ̶ 65%

Pharmacokinetic
linearity

Non linear

Drug interactions(in vitro)

Rifampicin induces
hepatic enzymes

Transporters

Solute carriertransporters (SLC)
ATP Binding Cassettetransporters (ABC)P-glycoprotein 1

Metabolizing
CYP450
enzymes*Information not available

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acetylators
15.5 L/hour: slow
NAT2 genotype
3.3 L/hour

41 L/hour

26.1 L/hour:
rapid/intermediate
NAT2 genotype
75 ̶ 95%

70–90%

60–80%

< 10%

< 10%

20%

NA*

NA*

NA*

Isoniazid is
CYP450 inducer
and inhibitor.

Pyrazinamide is aNA*xanthine
dehydrogenase/oxidase
substrate and aldehydeoxidase substrate

Isoniazid is aarylamine nacetyltransferase 2
substrate andinhibitorNA*

CYP450: 2C19,
3A4

NA*

NA*

Deamination followedby xanthine oxidase

NA*

Special populations
Rifampicin
The half-life of rifampicin has been reported to be longer in patients with liver impairment or biliary
obstruction.
The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily, andconsequently, no dosage adjustment is required. The half-life of rifampin at a dose of 720 mg daily has notbeen established in patients with renal failure. Following a single 900 mg oral dose of rifampin in patientswith varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to
5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to 50 mL/min, less than 30 mL/min,
and in anuric patients, respectively.
In one study, pediatric patients 6 to 58 months old were given rifampin suspended in simple syrup or as dry
powder mixed with applesauce at a dose of 10 mg/kg body weight. Peak serum concentrations of 10.7 ± 3.7
and 11.5 ± 5.1 mcg/mL were obtained 1 hour after preprandial ingestion of the drug suspension and theapplesauce mixture, respectively. After the administration of either preparation, the t1/2 of rifampin averaged
2.9 hours. It should be noted that in other studies in pediatric populations, at doses of 10 mg/kg body weight,
mean peak serum concentrations of 3.5 mcg/mL to 15 mcg/mL have been reported.
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Isoniazid
In slow acetylators with severely impaired renal function, accumulation of isoniazid may occur.
An impaired liver function prolongs the elimination half-life of isoniazid.
Ethambutol
Half is increased up to 8 hours in cases of renal impairment. Ethambutol is not removed from the blood byhaemodialysis.
Pyrazinamide
The plasma half-life may be prolonged in patients with impaired renal function.. Pyrazinamide is removed
from blood by haemodialysis.
Patients with hepatic cirrhotic insufficiency exhibit a marked reduction of the pyrazinamide clearance and anincrease in half-life. The area under the curve of pyrazinoic acid (the main metabolite) is increased threefold.
5.3

Preclinical safety data

Rifampicin
After oral administration of 100 mg/kg rifampicin for 6 months in rats, no toxic effects were observed. After
chronic administration of 200 mg/kg, swelling and hydropic degeneration of the liver were observed. Inmonkeys, vomiting, anorexia and weight loss were observed at chronic doses of 105 mg/kg/day. There islimited evidence for the carcinogenicity of rifampicin in mice. The available studies on mutagenicity indicate
an absence of a mutagenic effect.
An increased incidence of congenital malformations (principally spina bifida and cleft palate) has beenreported in the offspring of mice and rats given rifampicin in a dose of 150–250 mg/kg daily during
pregnancy. Defective osteogenesis and embryotoxicity occurred when rifampicin doses up to 20 times theusual daily human dose were used in pregnant rabbits.
Fertility and reproductive performance were not affected by oral administration of rifampicin to male andfemale rats at doses of up to one-third of the human dose.
Isoniazid
Non-clinical data reveal no special hazard for humans at recommended doses based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Treatment of pregnant rats with isoniazid resulted in reduced litter sizes and decreased postnatal growth,development, and cognitive ability in the offspring. Spermatogenesis impairment was observed in treatedrats.
Pyrazinamide
Pyrazinamide was not mutagenic in the Ames test. Pyrazinamide induced chromosomal aberrations in human
lymphocyte cell cultures. Pyrazinamide was not carcinogenic in rats or male mice when administered indaily doses of approximately 10–40 times the maximum recommended human dose; results in female mice
could not be determined because of insufficient numbers of surviving mice in the control group.
Studies in rats with pyrazinamide showed reduced concentrations of follicle-stimulating and luteinizing
hormones, oestrogen, and prolactin. In mice, oral dose levels of pyrazinamide approximately 12 times thoseused therapeutically did not have adverse effects on sperm production. High dose level studies in rats also
demonstrated decreased sperm production.
Ethambutol
Toxicological studies on high prolonged doses produced evidence of myocardial damage and heart failure,and depigmentation of the tapetum lucidum of the eyes in the dog. Degenerative changes in the central
nervous system, apparently not dose-related, have also been noted in dogs over a prolonged period. In therhesus monkey, neurological signs appeared after treatment with high doses given daily over several months.
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These were correlated with specific serum levels of ethambutol and with definite neuroanatomical changes in
the central nervous system.
Conflicting results are available on genotoxicity (negative Ames test, negative in human lymphocyte cell
cultures, positive in mouse micronucleus).
Cleft palate, exencephaly and vertebral column abnormalities have been observed with high doses in studies
in mice. Studies in rats and rabbits have shown that ethambutol in high doses causes minor abnormalities of
the cervical vertebrae, limb reduction defects, hare lip and cleft palate in the offspring. Ethambutol decreases
testosterone concentrations, spermatogenesis, and male fertility in high doses in rats when administered over
60 days.
A study in male rats determined that co-administration of four antituberculosis drugs, including ethambutol,
rifampicin, isoniazid, and pyrazinamide, produced a range of adverse effects on the testes and in sperm, as
well as an increase in pre- and post-implantation embryo lethality.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Core tablet:

Seal coating:
Film coating:Calcium stearate
Colloidal silicon dioxide,
Croscarmellose sodium,
Crospovidone,
Disodium edetate,
Maize starch,
Povidone,
Purified talc,
Shellac.
Hypromellose
Copovidone,
Polyvinyl alcohol
Titanium dioxide,
Talc,
Lecithin,
Xanthan gum
Colour Lake of sunset yellow

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
Alu/PVC/PVDC blister pack: 24 months
Alu/PVC/PE/PVDC blister pack: 36 months
Alu/Alu Strip pack: 36 months
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HDPE Bulk Pack: 24 months
6.4

Special precautions for storage

Blister pack: Stored in a dry place below 25°C and protect from light.
Strip Pack: Stored in a dry place below 30°C and protect from light.
For bulk HDPE bottle pack: Store at a temperature not exceeding 25° C in a dry place and protect from light.
6.5

Nature and contents of container

Transparent LDPE bag, containing 500 or 1000 tablets, packed in a triple laminated aluminium sachet which
is further packed in an HDPE bottle along with a leaflet. Each bottle is sealed with an aluminium tagger andclosed with a screw cap.
Alu/PVC/PVDC blister of 10 and 7 tablets. Such 10 blisters per box. Pack size: 100 (10 x 10) tablets and 70(10 x 7) tablets.
Alu/PVC/PVDC blister of 10 tablets. Such 10 blisters per box. Pack size: 100 tablets.
Alu/PVC/PVDC blister of 28 tablets. Such 3 or 24 blisters per box. Pack sizes: 84 (28 x 3) and 672 (28 x 24)
tablets.
Alu/Alu strip of 10 tablets. Such 10 strips in a carton. Pack sizes: 100 (10 x 10) tablets.
Alu/Alu strip of 12 tablets. Such 14 strips in a carton. Pack sizes: 168 (12 x 14) tablets.
Alu/Alu strip of 28 tablets. Such 3 or 24 strips in a carton. Pack sizes: 84 (3 x 28) and 672 (24 x 28) tablets.
Alu/PVC/PE/PVDC blister of 7 tablets. Such 10 blister per box. Pack size: 70 tablets (7 x 10)
Alu/PVC/PE/PVDC blister of 10 tablets. Such 10 blisters per box. Pack size: 100 tablets.
Alu/PVC/PE/PVDC blister of 28 tablets. Such 3, 6 or 24 blisters per box. Pack sizes: 84 (28 x 3), 168 (28 x 6)
and 672 (28 x 24) 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.

7.

SUPPLIER

Macleods Pharmaceuticals Ltd.
304, Atlanta Arcade,
Marol Church Road,
Andheri (East),
Mumbai- 400 059,
India
Tel: +91 022 66 76 28 00
Fax: +91 022 2821 65 99
Email: exports@macleodspharma.com
vijay@macleodspharma.com
sjadhav@macleodspharma.com

8.

WHO REFERENCE NUMBER (WHO Prequalification Programme)

TB168

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9.

WHOPAR Part 4

March 2023

DATE OF PREQUALIFICATION

7 March 2008

10.

DATE OF REVISION OF THE TEXTMarch 2023
References
WHO, Geneva, 2003: Treatment of Tuberculosis: Guidelines for national programmes
WHO, Geneva, 2006: Ethambutol efficacy and toxicity: literature review and recommendations for daily andintermittent dosage in children.
WHO consolidated guidelines on tuberculosis, Module 4: Treatment Drug-susceptible tuberculosis treatment(2022). Available at https://www.who.int/publications/i/item/9789240048126
WHO operational handbook on tuberculosis: Module 4: treatment: Drug-susceptible tuberculosis treatment(2022). Available at https://www.who.int/publications/i/item/9789240050761
WHO, Geneva, 2022. WHO consolidated guidelines on tuberculosis, Module 5: management of tuberculosis
in children and adolescent. Available at: https://apps.who.int/iris/rest/bitstreams/1414329/retrieve
WHO, Geneva, 2022. WHO operational handbook on tuberculosis, Module 5: management of tuberculosis inchildren and adolescents. Available at: https://apps.who.int/iris/rest/bitstreams/1414333/retrieve
ATS, CDC, and IDSA, Treatment of Tuberculosis, MMWR 2003; 52
Fixed-dose combination tablets for the treatment of tuberculosis Report of an informal meeting held in
Geneva Tuesday, 27 April 1999, World Health Organization Communicable Diseases Cluster 1999
Rimstar SPC. Available at:https://www.medicines.org.uk/emc/product/2999/smpc [accessed 26/11/2019]
Stockley’s Drug Interactions. Available at: www.medicinescomplete.com.
University of Liverpool HIV drug interactions site: hiv-druginteractions.org
Schaefer C, Peters P, Miller RK (eds). Drugs During Pregnancy and Lactation: Treatment Options and Risk
Assessment, 3rd edn. Amsterdam: Academic Press, 2015. Available at: https://doi.org/10.1016/B978-0-12408078-2.01001-5.
Kovalenko VM, Bondarenko LB, Byshovetz TF et al: Pyrazinamide Effects On Male Rat's Reproductive
Function. Toxicol Lett 2005;158(Suppl 1):S123.
Adebayo OA, Adesanoye OA, Abolaji OA, Kehinde AO, Adaramoye OA. First-line antituberculosis drugs
disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats. J Basic Clin Physiol
Pharmacol. 2018 Mar 28;29(2):131-140. doi: 10.1515/jbcpp-2017-0087. PubMed PMID: 29116933.
Shayakhmetova GM, Bondarenko LB, Voronina AK, Matvienko AV, Kitam V, Kovalenko VM. 2017.
Repeated administration of ethambutol in therapeuetic dose causes testes alteration and spermatogenesis
disruption in Wistar rats. Hum Exp Toxicol 36(5): 520-533.
Shayakhmetova GM, Bondarenko LB, Kovalenko VM. 2012. Damage of testicular cell macromolecules andreproductive capacity of male rats following co-administration of ethambutol, rifampicin, isoniazid andpyrazinamide. Interdiscip Toxicol 5(1): 9-14.

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