Rifampicin: SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

Enzyme Induction: Rifampicin accelerates the metabolism of Side-effects associated with rifampicin:
certain medicines by inducing microsomal enzymes, leading to Infections and infestations
decreases in plasma concentration of such medicines. The following side effects have been reported and the frequencies
Examples of medicines metabolised by cytochrome P-450 are not known:
enzymes are: anticonvulsants (e.g. phenytoin), antidysrhythmics Pseudomembranous colitis has been reported with rifampicin
{e.g. disopyramide, rnexiletine, quinidine, propafenone, therapy.
tocainide, verapamil), antioestrogens (e.g. tamoxifen, Skin and subcutaneous tissue disorders
toremifen} antipsychotics (e.g. haloperidol), oral anticoagulants The following side effects have been reported and the frequencies
(e.g. warfarin), antifungals (e.g. fluconazole, itramnazole, are not known:
ketoconazole), antiretrov1ral medicines (e.g. zidovudine, Some patients may experience a cutaneous syndrome which
saquinavir, indinavir, efavirenz). atovaquone, barbiturates presents 2 to 3 hours after a daily or intermittent dose i.e. facial
(e.g. hexobarbitone), beta-blockers, benzodiazepines flushing, urticaria, pruntus, erythema, rash, eye irritation.
srnrnUUMG STATIUS; [53] (e.g. diazepam), benzodiazep_ine·related medicines {e.g. zopiclone, More serious hypersensitivity cutaneous reactions may also occur,
P~OP'RffTARY MAME (and dosagJ: form): zolpidem}, calcium channel blockers (e.g. diltiazem, nifedipine, but are uncommon.
RU:AFOUR e·275 {ti.!blets) veraparnil), chloramphenicol, cimetidine, clarithromycin, Pemphigoid reactions, erythema multlforme including Stevens-
COMPOSITION: corticosteroids, cardiac glycosides (e.g. digoxin), clotibrate, Johnson syndrome, toxic epidermal necrolysis and vasculitis have
Each tablet contains: Rilampicin 150 mg systemic hormonal contraceptives, dapsone, doxycycline, been reported.
lsoniazid 75 mg oestrogens, ttuoroquinolones, gestrinone, oral hypoglycaemic Immune system disorders
Pyrazinamide 400 mg agents (sulfonylureas), immunosuppressive agents The following side effects have been reported and the frequencies
(e.g. azathloprine, cyclosporine, tacro!im_us} irinotecan, are not known:
Ethambutol HCI 275 mg levothyroxine, losartan, narcotic analgesics, methadone,
Contains sodium ascorbate as anti-oxidant. Lupus-like syndrome.
phenytoin, praziquantel, progestins, quinine, selective 5-HT3 A 12 hour "Hu" syndrome, usually occurring after 3 to 6 months
Excipients: receptor antagonists (e.g. ondansetron) statins metabolized
Core tablet: croscarmellose sodium, glyceryl behenate, lactose by CYP 3A4, sulphasalazine, teHthromycin, theophylline, of intermittent treatment and usually with doses_of 20 mg/kg
mono hydrate, magnesium stearate, maize starch, or more, may present as fever, chills, bone pain and malaise,
thiazolidinediones tricyclic antidepressants (e.g. amitryptyline, shortness of breath and wheezing; decrease in blood pressure -
polyvi nylpyrr:olidone and sodium Jauryl sulphate and sodium nortrypty!ine).
ascorbate as anti-oxidant. and shock: acute haemolytic anaemia; acute renal failure usually
Patients using systemic hormonal contraceptives should be due to acute tubular necrosis or to acute interstitial nephritis;
Film coating: polyvinyl alcohol, titanium dioxide, macrogol 3350, advised to change to non-hormonal methods of birth control
talc, Carmine FD&C Blue Indigo, Carmine Aluminium Lake and anaphylaxis.
during rifampicin therapy. (Refer to 'Warnings"). Gastrointestinal disorders
iron oxide black. When the two medicines were taken concomitantly, decreased
The tablets contain lactose monohydrate. The following side effects have been reported and the frequencies
concentrations of atovaquone and increased concentrations of are unknown:
PHARMACOLOGICAL CLASSIFICATION; rifampicin were observed. Rifampicin reduces serum atovaquone Nausea vomiting, anorexia, abdominal discomfort, diarrhoea
A20.2.3 Tuberculostatic combinations leve!s by about 50 %, whereas atovaquone modestly raises serum and epi'gastric distress, which may be alleviated by administration
PHARMACOLOGICAL ACTION: rifampicin levels. with food.
.. Rifafour e·275 Tablets is a combination of four first line agents Concurrent use of itraconazole, ketoconazole, voriconazole and Hepato-biliary disorders .
used in the treatment of tuberculosis. Rifampicin is a semi· rlfampidn has resulted in decreased serum concentrations of both The following side effects have been reported and the frequencies
synthetic, broad-spectrum bactericidal antibiotic. lsoniazid is a medicines. are unknown:
synthetic, antitubercular agent which is bacteriostatic against Concurrent use of rifampicin and enalapril has resulted in Hepatitis and the prodromal symptoms of hepatitis may occur
semi-dormant bacilli and bactericidal against actively dividing decreased concentrations of enalaprilat, the active metabolite of (nc1usea, vomiting, unusual tiredness/ fatigue). Liver function
mycobacteria. Pyrazinamide may be bactericida) or bacteriostatic, enalapril. Dosage adjustments should be made if indicated by the should be monitored. (See Warnings).
depending on its concentration and the susceptibility of the patient's clinical condition. Blood and the lymphatic system disorders _
organism. Ethambutol is a synthetic, bacteriostatic antitubercular When rifampicin is given concomitantly with either halothane The following side effects have been reported and the frequencies
agent. All agents are readily absorbed following oral or isoniazid, the potential for hepatotoxicity is increased. The are unknown:
administration, with wide distribution to most tissues and ttuids concomitant use of rifampicin and halothane should be avoided. Rlfampicin can cause thrombocytopenia and purpura usually
including cerebrospinal fluid. Patients receiving both rifampicin and isoniazid should be with intermittent regimens, but is reversible if the medicine is
INDICATIONS: monitored closely for hepatotoxicity. discontinued as soon as purpura occurs. Cerebral haemorrhage
Initial phase treatment of pulmonary and extrapulmonary Concurrent use of alcohol, palclcetamol and other hepatotoxic and fataliti~s__b~v~_ be~n reported ""._he_n.rifampicin a~~inistration
tuberculosis in new adult patients and re-treatment of adult cases. medication may increase the incidence ol rifampicin-induced
CONTRA-INDICATIONS: hepatotoxicity. The effectiveness of oestrogen-containing oral has been continued or resumed after the appearance of purpura.
Rifafou r e-275 Tablets are contra-indicated in: preparations is reduced. Disseminated intravascular coagulation has also been reported.
· patients with hypersensitivity to rifamycins, isoniazid, Therapeutic levels of rifampicin have been shown to inhibit Other haematological adverse effects include eosinophilia,
pyrazinamide, ethambutol or other chemically related standard microbiological assays for serum fo!ate and Vitamin B,,. leucopoenia and haemolytic anaemia. Agranulocytosis has been
medication; Thus, alternative assay methods should be considered. reported. Oedema and haemolysis have been reported.
- the presence of jaundice or active hepatic disease; Transient elevation of serum bilirubin has also been observed. Vascular disordel's
- patients with optic neuritis; Rifafour e-275 Tablets may impair biliary excretion of contrast The following side effects have been reported and the frequencies
- children under 13 years of age. media used for visualisation of the gallbladder, due to competition are unknown:
for biliary excretion. Therefore, these tests should be performed Disseminated intravascular coagulation has also been reported.
Rifafour e-275 is contra-indicated when given concurrently with
the com bi nation of saquinavir/ritonavir (See Interactions). before the morning dose of rifampicin. Nervous system disorders .
lsoniazid: · The following side effects have been reported and the frequencies
Rifampicin very markedly reduces ketoconazole levels. Rifampkin are unknown:
levels are halved by ketoconazole. (See Interactions}. Chronic use of isoniazid may decrease the plasma clearance
and prolong the duration of action of alfentanil, coumarin Headache, drowsiness, dizziness, ataxia, numbness, visual
WARNINGS; disturbances. Confusion and generalised numbness. Psychosis has
Liver function should be checked before and during treatment and anticoagulants, benzodiazepines, carbamazepine, phenytoln,
ethosuximide, chlorzoxazone, and theophylline. Appropriate been reported.
special care should be exercised in alcoholic patients, the elderly Musculoskeletal, connective 1issue and bone disorders
or those with pre-existing liver disease. adjustment of the anticonvulsant dose may be required.
Concurrent use of paracetamol, alcohol, rifampicin and other The following side effects have been reported and the frequencies
Caution should be observed with the use of Rifafour e-275 Tablets are unknown:
in the following patients: hepatotoxic medication, may increase the potential for isoniazid-
induced hepatotoxicity. Aluminium-containing antacids may Myopathy and muscular weakness.
- Impaired kidney function: dosage adjustment may be required Renal and urinary disorders
according to the serum concentration of ethambutol; , delay absorption ~nd decrease serum conc~ntrations o.t isonia.zid.
! Ingestion of certain types of cheese e.g. Swiss or Cheshire, or fish The following side effects have been reported and the frequencies
- Patients with visual detects: should visual disturbances occur e.g. tuna, may result in itching of the skin, rapid or pounding are unknown:
during treatment, these must be reported immediately and heart, chills or headache. Glucocorticoid corticosteroids may Alterations in kidney function and renal failure have occurred.
Rlfafour e-275 discontinued pending visual evaluation; increase hepatic metabolism and/or excretion of isoniazid. Reports of adrenal insufficiency in patients with compromised
- Patients at risk of neuropathy or pyridoxine deficiency, including Concurrent use of cycloserine, disulfiram and other neurotoxic adrenal function have been observed.
those who are diabetic, alcoholic, malnourished, uraemic or medicines may increase the potential for CNS toxicity. lsoniazid Reproductive system and breast disorders .
pregnant: pyridoxine supplementation (in a 10 mg to 50 mg daily may increase the formation of potentially nephrotoxic inorganic The following side effects have been reported and the frequencies
dose) is usually required in these instances; fluoride metabolites when used concurrently with entturane. are unknown:
· Patients with a history of gout; Interactions with .ketoconazole and miconazole have been Menstrual disturbances have been reported.
- Patients with porphyria; reported. False positive reactions with copper sulphate urine General disorders:
· Patients with epilepsy, as convulsions may be precipitated; glucose tests may occur. Rifampicin may produce reddish colouration of urine, sputum and
- Patients with a history of psychosis; Pyrazinamide: tears and the patient should be warned of this. Soft contact lenses
- Patients witfi diabetes: pyrazinamide may cause interference Pyrazinamlde may decrease the efficacy of gout therapy may be permanently stained. Blurred vision has been reported.
with urine ketone determinations; (e.g. a!Jopurinol, colchicine, probenecid or sulphinpyrazone) and Side-effects associated with isoniazid:
- Rifampicin may decrease the effect of oral contraceptives and dosage adjustments of this medication may be necessary. Hepato-biliary disorders .
patients are advised to change to non-hormonal methods of Ethambutol: The following side effects have been reported and the frequencies
birth control; Concurrent administration of neurotoxic medication with are unknown:
- Treatment with Rifafour e-275 Tablets may produce reddish ethambutol may potentiate neurotoxic effects such as optic and Elevated liver enzymes associated with clinical signs of hepatitis
colouration of urine, tears and saliva. Contact lenses may be peripheral neuritis. such as nausea, vomiting or fatigue may indicate hepatic damage.
irreversibly stained. PREGNANCY AND IACTATION: The incidence of liver damage is highest in patients over 35 years
- Concomitant antacid administration may reduce the absorption Safety in pregnancy has not been established. of age, those who are slow acety!ators and. those who cons.llrne
of rifampidn by up to about one-third. Dally doses of rifampicin All agents of Rlfafour e-275 Tablets are excreted in breast milk. alcohol on -a daily basis. Severe and sometimes fatal hepat1t1s can
should be given at least 1 hour before the ingestion of antacids. Safety during lactation has not been established. occur.
INTERACTIONS: When administered during the last weeks of pregnancy, rifampicin Gastrointestinal disorders
Rifampicin and isoniazid: can cause post-natal haemorrhages in the mother and infant, for The following side effects have been reported and the frequencies
When Rifafour e-275 is given concomitantly with the combination which treatment with vitamin Kmay be indicated. are unknown:
saquinavir/ritonavir, the potential for hepatotoxicity is increased. DOSAGE AND DIRECTIONS FOR USE: Nausea aiid vomiting, pancreatitis and epigastric distress.
Therefore, concomitant use of Rifafour e-275 with saquinavir/ Take Rifafour e-275 Tablets with a full glass of water 1 hour Metabolism a11d nutrition disorders
ritonavir is contra-indicated. (See Contra·I ndications). before, or 2 hours after a meal. However, if &astrointestinal The following side effects have been reported and the frequencies
Cytochrome P-450 Enzyme interaction: irritation occurs, the Tablets may be taken with .fo.od. If are unknown:
Rifampicin is known to induce and isoniazid is known to inhibit aluminium-containing antacids are taken, adminrster one hour Hyperglycaemia, metabolic acidosis. Pellagra.
certain cytochrome P-450 enzymes. Caution should be used when after the tablet dose. Immune system disorders .
prescribing Rifafour e-275 Tablets with medicines metabolised by The recommended treatment dosages, based on the patient's The following side effects have been reported and the lrequenctes
cytochrome P-450. To maintain optimum therapeutic blood levels, body weight, given daily for the 2 month initial-phase treatment are unknown:
dosages of rnedi,cines metabolised by these enzymes may require in adults and children over 13 years of age are as follows: Hypersensitivity reactions (skin eruptions inc.f~dlng erythema .
adjustment when starting or stopping concomitantly administered 30- 37 kg 2 Tablets multiforme,_fever, lymphadenopathy, vascul1t1s and anaphylax1s)
Rifafour e-275 Tablets. 38- 54 kg 3 Tablets may occur.
55- 70 kg 4 Tablets
71 kg and over 5 Tablets
 Blo.ocl and the lymphatic system disorders ..
The following side effects have been reported and the frequencies SPEOAIL P~E'CAUiW~JS;
are unknown: 1n the following cases, treatment with Rifafour e-275 Ta b/ets
Various haematological disturbances including anaemia, shoul~ be stopped immediately and the patient evaluated;
eosinophilia, sideroblastic anaemia, agranulocytosis, haemolytic jaundice, rash and fever, elevated liver enzymes associated with
,..anaemia, thrombocytopenia, neutropoenia, and less frequently, the clinical signs of hepatitis, visual impairment. If liver damage is
a plastic anaemia. confirmed, the medicine should not be recommenced.
Nervous system disorders Treatment should be discontinued permanently should
The following side effects have been reported and the frequencies thrombocytopenia, purpura, shock or renal failure occur.
are unknown: Periodic eye examinations during treatment are suggested.
Neurologi01! effects include psychotic.reactions and convulsions. As Rifafour e-275 Tablets contain lactose, patients with rare
The frequency of seizures may be increased in patients with hereditary problems of galactose intolerance, the Lapp lactase
epilepsy. · deficiency or glucose·galactose malabsorption should not take this
PolyneJJritis associated with isoniazid presenting as paraesthesia, medicine.
muscle weakness, loss ol tendon reflexes, etc. may occur. lsoniazid. has been associated with vertigo, visual disorders and
Peripheral neuropathy has also been associated with isoniazid psychotic reactions. (See Side-effects). Patients should be informed
administration. Pyridoxine supplementation prevents the of these, and advised that if affected, they should not drive,
development of peripheral neuritis, as well as most other operate machinery or take part in.any activities where these
nervous system dysfunctions. Optic neuritis and atrophy, memory symptoms may put either themselves or others at risk.
impairment, toxic psychosis a.nd toxic encephalopathy have also l(NOWN SVMPuOMS OF OVER.DOSAGE AND PART!CUlARS OF ITS
been reported. TREATMENT:
Musndoskeletal, connective tissue and bone disorders There is limited overdose information involving rifampicin,
The following side effects have been reported and the frequencies isoniazid, pyrazinamide and ethambutol in combination.
are unknown: Rifarnpidn:
Rheumatoid syndrome. Systemic lupus erythematosus-like Nausea, vomiting, abdominal pain, pruritus, headache and
syndrome. increasing lethargy will probably occur within a short time after
Rerial and urinary disorders acute ingtstion; unconsciousness may occur when there_ is_ severe
The following side effects have been reported and the frequencies hepatic disease. Transient increases in liver enzymes
are unknown: and/or bilirubin may occur. Brownish-red or orange _discoloration
Urinary retention. of the skin, urine, sweat, saliva, tears and faeces will occur and
Reproductive system <>nd bre<1st disorders its intensity is proportional to the amount ingested. Facial or
The following side effects have been reported and the frequencies periorbital oedema has also been reported in paediatric patients.
are unknown: Hypotension, sinus tachycardia, ventricular dysrhythmias, seizures.
I Gynaecomastia. and cardiac arrest were repo1ted in some fatal cases.
I Sl<in and subcutaneous tissue disorders Nonfatal acute overdoses in adults have been reported with doses
' Cutaneous reactions include rash, acne, Stevens Johnson ranging from 9 to 12 g rifampicin. Fatal acute overdoses~1n adults
syndrome, exfoliative dermatitis, pemphigus, lupus-like have been reported with doses ranging from 14 to·60 g. Nonfatal
I erythematosus-like reactions.
Side-effects assodated with pyrazinamide:
overdoses in paediatric patients ages 1 to 4 years old of 100 mg/kg
for one. or two doses have been reported.
Hepato-biliary disorders lsoniazid:
The following side effects have been reported and the frequencies lsoniazid overdosage produces signs and symptoms within
I are u'r1known: · 30 minutes to 3 hours after ingestion. Nausea, vomiting. dizziness,
I The most serious side effect is hepatotoxicity and its frequency slurring of speech, blurring of visior:i and ·visual hallucination.$
appears to be dose-related. It varies from a symptom.less are among the early manifestations. With marked overdosage,
abnormality of hepatic cell function through a mild syndrome respiratory distress and CNS depression, progressing rapidly from
of fever, malaise and liver tenderness, to more serious reactions stupor lo profound coma are to be expected, along with severe,
such as clinical jaundice and rare cases of acute yellow atrophy intractable seizures. Severe metabolic acidosis, acetonuria and
and death. hyp"erglycaemia are typical laboratory findings.
Musculoskeletal, connective tissue and bone disorders Pyrazinamide:
Common: Hyperuricaernia, occasionally accompanied by There is limited information related to pyrazinamide overdosage. ·
arthralgia and may lead to attacks of gout. Liver toxicity and hyperuricaemia may occur with overdosage.
Skin and subcutaneous tissue disorder 1 Ethambutol:
The following side effects have been reported and the frequencies There is limited information related to ethambutol overdose.
are unknown: Loss of appetite, gastro-intestinal disturbances, fever, headache,
Photosensitivity, pruritus, erythema and skin rash have been dizziness, confusion and hallucinations may occur.
reported. Management: ·
R"are: angioedema has been reported. In case of overdosage with Rifafour e-275, gastric lavage should
Gastrointestinal disorders . be performed as soon as possible. Following evacuation of the
The following side effects have been reported and the frequencies gastric contents, the insta!lation:of activated charcoal slurry into
are unknown: the stomach may help absorb any remaining medicine from the
Anorexia, nausea and vomiting and aggravation of peptic ulc~r. gastrointestinal tract. Antiemetic medication rriay be required to·
General disorders control severe nausea and vomiting.
The fol!owing side effects have been reported and the frequencies Intensive support measures should be instituted, ini:;!uding airwa·y
are unknown: patency and individual symptoms treated as they arise. ··
Malaise, fever. IDENTIFICATION
Blood and 1he lymphatic system disorders Purple, round, film coated Tablets.
The following side effects have been reported and the frequencies PRESENTATION .
are unknown: Packs of 28, 56, 84, ioo and 112 Tablets in foil-foil blisters. Not all
Siderobl~stic anaemia, thrombocytopaenia with or without pack sizes are marketed.
purpura. STORAGE INSTRUCTIONS:
Renal and urinary disorders Store in a coo! place, below 25 °C in \veil-closed containers,
The following side effects have been reported and the frequencies protected from light.
are unknown: l(E.IEP OUT OF REACH.OF CHJLDRri;N,
Dysuria. REGISTRATION NUMBER:
Side.effects associated with ethambutol: 34/20.2.3/0187
Nervous system disorders NAME AND BUSINESS AOIJR.IESS OF THE APPLICANT:
The following side effects have been .reported and the frequencies sanofi-aventis south africa (pty} ltd.
are unknown: 2 Bond Street
Retrobulbar neuritis with a reduction in visual acuity, constriction Mid rand
of visual field, central or peripheral scotoma, and green-red colour South Africa
blindness may occur, affecting one or both eyes. The degree of 1685
visual impairment appears to depend on the dose and duration of DAH OF PUBLICATION OF THIS PACKAGE INSERT:
therapy. Retinal haemorrhage has occurred less frequently. 19April2D13
Peripheral neuritis, confusion, disorientation, hallucinations;
headache, dizziness and malaise.
Renal and urinary disorders
The following sidle effects have been reported and the frequencies
are unknown:
Renal clearance of urate may be reduced and acute gout has been
precipitated.
General disorders
The following side effects have been .reported and the frequencies
are unknown:
Hypersensitivity reactions include skin rash, pruritus, fever and
joint pains. ·
Blood ,md the lymphatic system disorders
Leucopoenia.
Gastrointestinal disorders
The folloWing side effects have been reported and the frequencies
are unknown:
Gastrointestinal disturbances include metallic taste, nausea,
vomiting, anorexia and abdominal pain.
Hepato-biliary disorders .
The following side effects have been reported and the frequencies
are unknown:
Jaundice or transient liver dysfunction.
sanoti-aventis south africa (pty) ltd.
2 Bond Street
Mid rand
South Africa
·1685