4.1. Therapeutic indications

Indications for use

Tuberculosis: In combination with other active anti-tuberculosis drugs in the treatment of all forms of tuberculosis, including fresh, advanced, chronic and drug-resistant cases. Rifadin is also effective against most atypical strains of Mycobacteria.

Leprosy: In combination with at least one other active anti-leprosy drug in the management of multibacillary and paucibacillary leprosy to effect conversion of the infectious state to a non-infectious state.

Other Infections: In the treatment of Brucellosis, Legionnaires Disease, and serious staphylococcal infections. To prevent emergence of resistant strains of the infecting organisms, Rifadin should be used in combination with another antibiotic appropriate for the infection.

Prophylaxis of meningococcal meningitis: For the treatment of asymptomatic carriers of N. meningitidis to eliminate meningococci from the nasopharynx.

Haemophilus influenzae: For the treatment of asymptomatic carriers of H. influenzae and as chemoprophylaxis of exposed children, 4 years of age or younger.

4.2. Posology and method of administration

Posology

The daily dose of Rifadin, calculated from the patient's body weight, should preferably be taken at least 30 minutes before a meal or 2 hours after a meal to ensure rapid and complete absorption.

Tuberculosis

Rifadin should be given with other effective anti-tuberculosis drugs to prevent the possible emergence of rifampicin-resistant strains of Mycobacteria.

Adults: The recommended single daily dose in tuberculosis is 8 – 12 mg/kg.

Usual Daily dose:

Patients weighing less than 50 kg – 450 mg.

Patients weighing 50 kg or more – 600 mg.

Children: In children, oral doses of 10 – 20 mg/kg body weight daily are recommended, although a total daily dose should not usually exceed 600 mg.

Leprosy

600 mg doses of rifampicin should be given once per month. Alternatively, a daily regimen may be used. The recommended single daily dose is 10 mg/kg.

Usual daily dose:

Patients weighing less than 50 kg – 450 mg.

Patients weighing 50 kg or more – 600 mg.

In the treatment of leprosy, rifampicin should always be used in conjunction with at least one other anti-leprosy drug,

Brucellosis, Legionnaires Disease or serious staphylococcal infections

Adults: The recommended daily dose is 600 – 1200 mg given in 2 - 4 divided doses, together with another appropriate antibiotic to prevent the emergence of resistant strains of the infecting organisms.

Prophylaxis of meningococcal meningitis

Adults: 600 mg twice daily for 2 days.

Children (1 – 12 years): 10 mg/kg twice daily for 2 days.

Children (3 months – 1 year): 5 mg/kg twice daily for 2 days.

Prophylaxis of Haemophilus influenzae

Adults and children: For members of households exposed to H. influenzae B disease when the household contains a child 4 years of age or younger, it is recommended that all members (including the child) receive rifampicin 20 mg/kg once daily (maximum daily dose 600 mg) for 4 days. Index cases should be treated prior to discharge from hospital.

Neonates (1 month): 10 mg/kg daily for 4 days.

Impaired liver function:

A daily dose of 8 mg/kg should not be exceeded in patients with impaired liver function.

Use in the elderly:

In elderly patients, the renal excretion of rifampicin is decreased proportionally with physiological decrease of renal function; due to compensatory increase of liver excretion, the terminal half-life in serum is similar to that of younger patients. However, as increased blood levels have been noted in one study of rifampicin in elderly patients, caution should be exercised in using rifampicin in such patients, especially if there is evidence of impaired liver function.

Method of administration

For oral administration.

4.3. Contraindications

Rifadin is contraindicated:

• in patients who are hypersensitive to the rifamycins or any of the excipients (see section 6.1)

• in the presence of jaundice

• concurrent treatment with the combination of saquinavir/ritonavir (see section 4.5)

• with medicines strongly affected by its potential to induce drug metabolizing enzymes and transporters such as:

- lurasidone

- sofosbuvir, daclatasvir, and telaprevir

- cabotegravir, fostemsavir and lenacapavir

(see section 4.5)

4.4. Special warnings and precautions for use

Rifampicin should be given under the supervision of a respiratory or other suitably qualified physician.

Cautions should be taken in case of renal impairment if dose > 600 mg/day. All tuberculosis patients should have pre-treatment measurements of liver function.

Adults treated for tuberculosis with rifampicin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in children unless a complicating condition is known or clinically suspected.

All patients with abnormalities should have follow up examinations, including laboratory testing, if necessary.

Patients with impaired liver function should only be given rifampicin in cases of necessity, and then with caution and under close medical supervision. In these patients, lower doses of rifampicin are recommended and careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) should initially be carried out prior to therapy, weekly for two weeks, then every two weeks for the next six weeks. If signs of hepatocellular damage occur, rifampicin should be withdrawn.

Rifampicin should also be withdrawn if clinically significant changes in hepatic function occur. The need for other forms of antituberculosis therapy and a different regimen should be considered. Urgent advice should be obtained from a specialist in the management of tuberculosis. If rifampicin is re-introduced after liver function has returned to normal, liver function should be monitored daily.

In patients with impaired liver function, elderly patients, malnourished patients, and possibly, children under two years of age, caution is particularly recommended when instituting therapeutic regimens in which isoniazid is to be used concurrently with Rifadin. If the patient has no evidence of pre-existing liver disease and normal pre-treatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient's condition occur.

Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions.

In some patients hyperbilirubinaemia can occur in the early days of treatment. This results from competition between rifampicin and bilirubin for hepatic excretion. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather the decision should be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient's clinical condition.

Cases of drug-induced liver injury, including fatal cases (especially when used in combination with other anti-tuberculosis drugs), have been reported in patients treated with rifampicin with an onset of a few days to a few months following treatment initiation. Signs and symptoms include elevated serum hepatic enzymes, cholestatic jaundice, hepatitis, hepatotoxicity, hepatocellular injury, and mixed liver injury. Most patients recovered on discontinuation of rifampicin treatment; nevertheless, progression to acute liver failure requiring liver transplantation can occur. The mechanism of rifampicin-induced liver injury is not clearly elucidated, but data indicate either an immuno-allergic mechanism or direct toxicity of metabolic products. Patients should be instructed to contact their physician in case symptoms suggestive of liver injury occur. In such patients rifampicin should be discontinued and liver function should be assessed. Rifampicin should not be re-introduced in patients with an episode of hepatic injury during treatment with rifampicin for which no other cause of liver injury has been determined.

Because of the possibility of immunological reaction including anaphylaxis (see section 4.8) occurring with intermittent therapy (less than 2 - 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment.

Rifampicin has enzyme induction 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.

Cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS), including fatal cases, have been reported with Rifadin Oral Suspension use. If laboratory or clinical findings associated with TMA occur in a patient receiving Rifadin Oral Suspension, treatment should be discontinued and thorough evaluation for TMA performed, including platelet levels, renal function, serum lactate dehydrogenase (LDH) and a blood film for schistocytes (erythrocyte fragmentation). ADAMTS13 activity and anti-ADAMTS13-antibody determination should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with Rifadin Oral Suspension should not be resumed and patients should be treated accordingly (consider plasma exchange).

Severe, systemic hypersensitivity reactions, including fatal cases, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been observed during treatment with anti-tuberculosis therapy (see section 4.8). It is important to note that early manifestations of hypersensitivity, such as fever, lymphadenopathy or biological abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be advised to consult immediately their physician.

Rifadin Oral Suspension should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Paradoxical drug reaction

After initial improvement of tuberculosis under therapy with Rifadin Oral Suspension, the symptoms may worsen again. In affected patients, clinical or radiological deterioration of existing tuberculous lesions or the development of new lesions have been detected. Such reactions have been observed within the first few weeks or months of initiation of tuberculosis therapy. Cultures are usually negative, and such reactions do not usually indicate treatment failure.

The cause of this paradoxical reaction is still unclear, but an exaggerated immune reaction is suspected as a possible cause. In case a paradoxical reaction is suspected, symptomatic therapy to suppress the exaggerated immune reaction should be initiated if necessary. Furthermore, continuation of the planned tuberculosis combination therapy is recommended.

Patients should be advised to seek medical advice immediately if their symptoms worsen. The symptoms that occur are usually specific to the affected tissues. Possible general symptoms include cough, fever, tiredness, breathlessness, headache, loss of appetite, weight loss or weakness (see section 4.8).

Severe cutaneous adverse reactions (SCARs) including Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with a not known frequency in association with Rifadin Oral Suspension treatment.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Rifadin Oral Suspension should be withdrawn immediately and an alternative treatment considered (as appropriate).

Most of these reactions occurred within 2 days to 2 months after treatment initiation; the time to onset can vary depending on the conditions.

Rifadin Oral Suspension may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum and tears, and the patient should be forewarned of this. Soft contact lenses have been permanently stained (see section 4.8).

Rifadin Oral Suspension is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease or increase concomitant drug exposure, safety and efficacy (see section 4.5). Therefore, potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment.

Rifampicin may cause vitamin K dependent coagulopathy and severe bleeding (see section 4.8). Monitoring of occurrence of coagulopathy is recommended for patients at particular bleeding risk. Supplemental vitamin K administration should be considered when appropriate (vitamin K deficiency, hypoprothrombinemia).

There have been reports of interstitial lung disease (ILD) or pneumonitis in patients receiving Rifadin Oral Suspension for treatment of tuberculosis (see section 4.8). ILD/pneumonitis is a potentially fatal disorder. Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea accompanied by dry cough) and fever should be performed to confirm the diagnosis of ILD/pneumonitis. If ILD/pneumonitis is diagnosed, Rifadin Oral Suspension should be permanently discontinued in case of severe manifestations (respiratory failure and acute respiratory distress syndrome) and appropriate treatment initiated as necessary.

Excipients

Ethanol: This medicinal product contains 28.5 mg of alcohol (ethanol) in each 30 ml dose which is equivalent to 0.95 mg/ml (0.1% w/v). The amount in 30 ml of this medicinal product is equivalent to less than 1 ml beer or wine. The small amount of ethanol in this medicinal product will not have any noticeable effects.

Sucrose: This medicinal product contains 12 g of sucrose per 30 ml dose. This should be taken into account in patients with diabetes mellitus. This may also be harmful to teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per daily dose, that is to say essentially 'sodium-free'.

Potassium: This medicinal product contains less than 1 mmol (or 10.4 mg) potassium per 30 ml dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Metabisulfite: This medicinal product contains sodium metabisulfite which may cause allergic type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people.

Parahydroxybenzoate: This medicinal product contains methyl-p-hydroxybenozoate and propyl-p-hydroxybenzoate, these may cause allergic reactions (possibly delayed).

4.5. Interaction with other medicinal products and other forms of interaction

Interference with laboratory and diagnostic tests

Therapeutic levels of rifampicin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Thus, alternative assay methods should be considered. Transient elevation of BSP and serum bilirubin has been reported. Rifampicin may impair biliary excretion of contrast media used for visualization of the gallbladder, due to competition for biliary excretion. Therefore, these tests should be performed before the morning dose of rifampicin.

Pharmacodynamic Interactions

When rifampicin is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifadin with saquinvir/ritonavir is contraindicated (see section 4.3).

When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampicin and halothane should be avoided. Patients receiving both rifampicin and isoniazid should be monitored closely for hepatotoxicity.

The concomitant use of rifampicin with other antibiotics causing vitamin K dependent coagulopathy such as cefazolin (or other cephalosporins with N-methyl-thiotetrazole side chain) should be avoided as it may lead to severe coagulation disorders, which may result in fatal outcome (especially in high doses).

Effect of Rifadin Oral Suspension on other medicinal products

Induction of Drug Metabolizing Enzymes and Transporters

Rifadin Oral Suspension is a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifadin Oral Suspension include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most drugs are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced by Rifadin Oral Suspension simultaneously. Therefore, Rifadin Oral Suspension may accelerate the metabolism and decrease the activity of certain co-administered drugs, or increase the activity of a coadministered pro-drug (where metabolic activation is required) and has the potential to perpetuate clinically important drug-drug interactions against many drugs and across many drug classes (Table 1). To maintain optimum therapeutic blood levels, dosages of drugs may require adjustment when starting or stopping concomitantly administered Rifadin Oral Suspension.

Rifampicin is contraindicated with medicines strongly affected by its potential to induce drug metabolizing enzymes and transporters such as: lurasidone, sofosbuvir, daclatasvir, telaprevir, cabotegravir, fostemsavir and lenacapavir. Significant decrease in their plasma concentrations is observed because of potent induction of CYP 3A4, P-gp, UGT1A1 by rifampicin which is likely to result in loss of their therapeutic effectiveness.

Examples of drugs or drug classes affected by rifampicin:

• Antiarrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide)

• Antiepileptics (e.g. phenytoin)

• Hormone antagonist (anti-oestrogens e.g. tamoxifen, toremifene, gestinone)

• Antipsychotics (e.g. haloperidol, aripiprazole)

• Anticoagulants (e.g. coumarins)

• Antivirals (e.g. saquinavir, indinavir, efavirenz, cabotegravir, fostemsavir, lenacapavir, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine)

• Barbiturates

• Beta-blockers (e.g. bisoprolol, propanolol)

• Anxiolytics and hypnotics (e.g. diazepam, benzodiazepines, zopiclone, zolpidem)

• Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine)

• Anti-bacterials (e.g. chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin)

• Corticosteroids

• Cardiac glycosides (digitoxin, digoxin)

• Clofibrate

• Immunosuppressive agents (e.g. ciclosporin, sirolimus, tacrolimus)

• Irinotecan

• Thyroid hormone (e.g. levothyroxine)

• Losartan

• Analgesics (e.g. methadone, narcotic analgesics)

• Praziquantel

• Quinine

• Riluzole

• Selective 5-HT3 receptor antagonists (e.g. ondansetron)

• Statins metabolised by CYP 3A4 (e.g. simvastatin)

• Theophylline

• Tricyclic antidepressants (e.g. amitriptyline, nortriptyline)

• Cytotoxics (e.g. imatinib)

• Diuretics (e.g. eplerenone)

Cabotegravir, fostemsavir, lenacapavir: Rifampicin 600 mg daily reduced cabotegravir exposure (AUC) by 59% most likely via induction of UGTs.

Rifampicin 600 mg daily reduced fostemsavir exposure (AUC) by 82% most likely via induction of CYP3A4.

Rifampicin 600 mg daily reduced lenacapavir exposure (AUC) by 84% most likely via induction of CYP3A4, UGT1A1 and P-gp.

Lurasidone: Rifampicin 600mg was shown to decrease lurasidone AUC by 81%. Therefore, markedly reduced exposure of lurasidone can be expected when lurasidone is given concomitantly with a CYP3A4 inducer such as rifampicin (see section 4.3).

Enalapril: Decrease enalapril active metabolite exposure. Dosage adjustments should be made if indicated by the patient's clinical condition

Hepatitis-C antiviral drugs (e.g, daclatasvir, simeprevir, sofosbuvir, telaprevir): Concurrent use of treatment of simeprevir and rifampicin should be avoided. For daclatasvir, sofosbuvir and telaprevir see section 4.3.

Morphine: Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored, and doses of rifampicin adjusted during and after treatment with rifampicin.

Clopidogrel: Increases active metabolite exposure. Rifadin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of clopidogrel and rifampicin should be discouraged.

Dapsone: Rifampicin has also been shown to increase the clearance of dapsone and the production of the hydroxylamine metabolite of dapsone which could increase the risk of methaemoglobinaemia, haemolytic anaemia, agranulocytosis, and haemolysis.

Systemic hormonal contraceptives including oestrogens and progestogens: Rifampicin treatment reduces the systemic exposure of oral contraceptives. Patients on oral contraceptives should be advised to use alternative, non-hormonal methods of birth control during Rifadin therapy.

Mifepristone: Rifampicin was shown to decrease mifepristone AUC by 6.3-fold and its metabolites 22-hydroxy mifepristone and N-demethyl mifepristone by 20-fold and 5.9-fold, respectively. Therefore, reduced efficacy can be expected when mifepristone is given concomitantly with a potent CYP inducer such as rifampicin.

Antidiabetic (e.g. chlorpropamide, tolbutamide, sulfonylureas, rosiglitazone): diabetes may become more difficult to control.

Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole, caspofungin): Concurrent use of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs. After two weeks of repeated administration of rifampicin, trough levels of caspofungin were 30% lower than in adult subjects who received caspofungin alone.

If p-aminosalicylic acid and rifampicin are both included in the treatment regimen, they should be given not less than eight hours apart to ensure satisfactory blood levels.

Effect of other medicinal products on Rifadin Oral Suspension

Antacids: Concomitant antacid administration may reduce the absorption of rifampicin. Daily doses of rifampicin should be given at least 1 hour before the ingestion of antacids.

Paracetamol: Concomitant use of paracetamol with rifampicin may increase the risk of hepatotoxicity.

Other drug interactions with Rifadin Oral Suspension

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed.

4.6. Fertility, pregnancy and lactation

Pregnancy

At very high doses in animals, rifampicin has been shown to have teratogenic effects. There are no well controlled studies with rifampicin in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human fetus is not known.

Therefore, Rifadin should be used in pregnant women or in women of child bearing potential only if the potential benefit justifies the potential risk to the foetus.

When Rifadin is administered during the last few weeks of pregnancy it may cause post-natal haemorrhages in the mother and infant for which treatment with Vitamin K1 may be indicated.

Breast-feeding

Rifampicin is excreted in breast milk, patients receiving rifampicin should not breast-feed unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant.

4.7. Effects on ability to drive and use machines

None stated

4.8. Undesirable effects

The following CIOMS frequency rating is used, when applicable:

Very common (≥ 1/10); Common (≥ 1/100 to < 1/ 10); Uncommon (≥ 1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from available data).

Reactions occurring with either daily or intermittent dosage regimens include:

System organ class

Frequency

Preferred Term

Infections and infestations

Not known

Pseudomembranous colitis

Influenza

Blood and lymphatic system disorders

Common

Thrombocytopenia with or without purpura, usually associated with intermittent therapy, but is reversible if drug is discontinued as soon as purpura occurs.

Uncommon

Leukopenia

Not known

Thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uremic syndrome

Disseminated intravascular coagulation

Eosinophilia

Agranulocytosis

Haemolytic anaemia

Vitamin K dependent coagulation disorders

Immune system disorders

Not known

Anaphylactic reaction

Endocrine disorders

Not known

Adrenal insufficiency in patients with compromised adrenal function have been observed

Metabolism and nutritional disorders

Not known

Decreased appetite, hyperuricaemia

Psychiatric disorders

Not known

Psychotic disorder

Nervous system disorders

Common

Headache

Dizziness

Not known

Cerebral haemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura

Eye disorders

Not known

Tear discolouration

Vascular disorders

Not known

Shock

Flushing

Vasculitis

Bleeding

Respiratory, thoracic and mediastinal disorders

Not known

Dyspnoea

Wheezing

Sputum discoloured

Interstitial lung disease (including pneumonitis)

Gastrointestinal disorders

Common

Nausea

Vomiting

Uncommon

Diarrhoea

Not known

Gastrointestinal disorder

Abdominal discomfort

Tooth discolouration (which may be permanent)

Hepatobiliary disorders

Not known

Drug-induced liver injury (including fatal cases especially when used in combination with other anti-tuberculosis drugs)

Hepatitis

Hyperbilirubinaemia (see section 4.4)

Skin and subcutaneous tissue disorders

Not known

Erythema multiforme

Stevens-Johnson syndrome (SJS)

Toxic epidermal necrolysis (TEN)

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Acute generalized exanthematous pustulosis (AGEP) (see section 4.4)

Skin reaction

Pruritus

Rash pruritic

Urticaria

Dermatitis allergic

Pemphigoid

Sweat discoloration

Musculoskeletal and connective tissue disorders

Not known

Muscle weakness

Myopathy

Bone pain

Renal and urinary disorders

Not known

Acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis

Chromaturia

Pregnancy, puerperium and perinatal conditions

Not known

Post-partum haemorrhage

Fetal-maternal haemorrhage

Reproductive system and breast disorders

Not known

Menstrual disorder

Congenital, familial and genetic disorders

Not known

Porphyria

General disorders and administration site conditions

Very common

Pyrexia

Chills

Common

Paradoxical drug reaction (Recurrence or appearance of new symptoms of tuberculosis, physical and radiological signs in a patient who had previously shown improvement with appropriate anti-tuberculosis treatment is called a paradoxical reaction, which is diagnosed after excluding poor compliance of the patient to treatment, drug resistance, side effects of antitubercular therapy, secondary bacterial/fungal infections).*

Not known

Oedema

Investigations

Common

Blood bilirubin increased

Aspartate aminotransferase increased

Alanine aminotransferase increased

Unknown

Blood pressure decreased

Blood creatinine increased

Hepatic enzyme increased

*Incidence of paradoxical drug reaction: Lower frequency is reported as 9.2% (53/573) (data between October 2007 and March 2010) and higher frequency is reported as 25% (19/76) (data between 2000 and 2010).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Human Experience

Signs and Symptoms

Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within a short 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 paediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, 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 - 12 g rifampicin. Fatal acute overdoses in adults have been reported with doses ranging from 14 – 60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in paediatric patients ages 1 - 4 years old of 100 mg/kg for one to two doses have been reported.

Management

Intensive supportive measures should be instituted and individual symptoms treated as they arise. Since nausea and vomiting are likely to be present, gastric lavage is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach 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.