4.1. Therapeutic indications

Rifater is indicated in the treatment of pulmonary tuberculosis.

4.2. Posology and method of administration

Posology

Rifater is recommended in the initial intensive phase of the short-course treatment of pulmonary tuberculosis. During this phase, which lasts for 2 months, Rifater should be administered on a daily continuous basis. The concomitant administration of ethambutol or intramuscular streptomycin over the same period of time is advised.

Each Rifater tablet contains isoniazid (INH), pyrazinamide (Z) and rifampicin (RAMP) in such a ratio that the administration of 9 – 12 mg/kg RAMP, 4 – 5 mg/kg INH and 23 – 30 mg/kg Z can be achieved by giving 3 tablets daily to patients weighing less than 40 kg, 4 tablets to patients weighing 40 – 49 kg, 5 tablets to patients weighing 50 – 64 kg and 6 tablets to patients weighing 65 kg or more.

Rifater should be given as a single dose and preferably on an empty stomach at least 30 minutes before a meal, or 2 hours after a meal to ensure rapid and complete absorption.

Once the initial intensive phase of treatment has been completed treatment can be continued with the combination rifampicin-isoniazid (Rifinah) always on a daily basis.

This regimen, if correctly applied, is 100% effective with very few, if any, relapses. The clinical evidence indicates that these occur generally in the first 6 months after stopping treatment with bacilli fully sensitive to the drugs employed, so that changes in the drugs to be utilised for further treatment are not required. The regimen has been found to be fully effective also in the presence of a bacillary population resistant to isoniazid, to streptomycin or to both drugs.

Children: The ratio of the three drugs in Rifater may not be appropriate in children (eg higher mg/kg doses of INH are usually given in children than in adults). Rifater can be used only in special cases, after careful consideration of the mg/kg dose of each component.

Use in the elderly: Caution should be exercised in such patients, in view of the possible decrease of the excretory function of the kidney and of the liver.

Method of administration

For oral administration.

4.3. Contraindications

Rifater is contraindicated:

• in patients who are hypersensitive to any one of the components of the combination 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

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

The precautions for the use of Rifater are the same as those considered when a triple individual administration of rifampicin, isoniazid and pyrazinamide is required. Rifater should only be given under supervision.

Warnings and precautions associated with rifampicin, isoniazid and pyrazinamide, alone or in combination

Each of these drugs has been associated with liver dysfunction. All tuberculosis patients should have pre-treatment measurements of liver function.

Adults treated for tuberculosis with Rifater should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count and a platelet count (or estimate).

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

All patients with abnormalities should have follow-up, including laboratory testing, if necessary. However, because there is a higher frequency of isoniazid-associated hepatitis among persons older than 35 years of age, a transaminase measurement should be obtained at baseline and at least monthly during therapy in this age group. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease, intravenous drug use and being a black or Hispanic woman.

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.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with Rifater treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

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

If signs and symptoms suggestive of these reactions appear, Rifater should be withdrawn immediately and an alternative treatment considered.

If the patient has developed a serious reaction such as SJS, TEN or AGEP with the use of Rifater, treatment with Rifater must not be restarted in this patient at any time.

Cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS), including fatal cases, have been reported with Rifater use. If laboratory or clinical findings associated with TMA occur in a patient receiving Rifater, 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 Rifater should not be resumed and patients should be treated accordingly (consider plasma exchange).

Paradoxical drug reaction

After initial improvement of tuberculosis under therapy with Rifater, 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).

Patients with impaired liver function should only be given Rifater in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every two to four weeks during therapy.

If signs of hepatocellular damage or clinically significant changes in hepatic function occur, Rifater should be withdrawn. 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 Rifater is reintroduced after liver function has returned to normal, liver function should be monitored daily.

Rifater should be discontinued if an alternative etiology for the signs and symptoms cannot be established.

Warnings and precautions associated with rifampicin

Cautions should be taken in cases of renal impairment if dose > 600 mg/day.

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 rifampicin.

In some cases, hyperbilirubinaemia resulting from competition between rifampicin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. 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 rifampicin therapy (less than 2 or 3 per week) patients should be closely monitored. Patients should be cautioned against interruption of dosage regimens since these reactions may occur.

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.

Rifampicin 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)

Rifampicin 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 whether 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 rifampicin for treatment of tuberculosis. 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, rifampicin should be permanently discontinued in case of severe manifestations (respiratory failure and acute respiratory distress syndrome) and appropriate treatment initiated as necessary.

Warnings and precautions associated with isoniazid

Cerebellar syndrome (including cerebellar ataxia, ataxia, dysdiadochokinesis, balance disorders, nystagmus, dysmetria) has been reported with the use of isoniazid mainly in patients with chronic kidney disease (see section 4.8).

Use of isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction.

Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Therefore, patients should be monitored for the prodromal symptoms of hepatitis; such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

Care should be exercised in the treatment of elderly or malnourished patients who may also require Vitamin B6 supplementation with the isoniazid therapy.

Use of isoniazid should be carefully monitored in patients with slow acetylator status, epilepsy, history of psychosis, history of peripheral neuropathy, diabetes, alcohol dependence, HIV infection or porphyria.

Warnings and precautions associated with pyrazinamide

Rifater should be used with caution in patients with a history of gout. If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing pyrazinamide (e.g. Rifinah 150 or 300).

The possibility of pyrazinamide having an adverse effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.

Excipients

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

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.

Interactions with other medicinal products

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

Cytochrome P-450 enzyme interaction

Rifampicin is known to induce, and isoniazid is known to inhibit certain cytochrome P-450 enzymes. In general, the impact of the competing effects of rifampicin and isoniazid on the metabolism of drugs that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing Rifater with drugs metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, dosages of drugs metabolised by these enzymes may require adjustment when starting or stopping Rifater.

Interactions with rifampicin

Pharmacodynamic Interactions

The potential for hepatotoxicity is increased with an anaesthetic.

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 (specially with high doses).

Effect of rifampicin on other medicinal products

Induction of Drug Metabolizing Enzymes and Transporters

Rifater is a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifater 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 Rifater simultaneously. Therefore, Rifater may accelerate the metabolism and decrease the activity of certain co-administered drugs, or increase the activity of a co-administered 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 Rifater.

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 Rifater:

• 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)

• Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole, caspofungin)

• 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 morphine adjusted during and after treatment with rifampicin.

Clopidogrel: Increases active metabolite exposure. Rifater 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 using oral contraceptives should be advised to change to non-hormonal methods of birth control during Rifater 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.

Rifampicin may reduce the effect of ACE inhibitors (e.g. enalapril, imidapril), antiemetics (e.g. aprepitant), antineoplastic agents (e.g. imatinib), diuretics (e.g. eplerenone), drugs used in erectile dysfunction (e.g. tadalafil), oral hypoglycaemic agents (e.g. nateglinide, repaglinide) and NSAIDS (e.g. etoricoxib).

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.

Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole, caspofungin): After two weeks of repeated administration of rifampicin, trough levels of caspofungin were 30% lower than in adult subjects who received caspofungin alone.

Effect of other medicinal products on rifampicin

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 rifampicin

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

Interactions with isoniazid

The following drugs may interact with isoniazid:

• Antiepileptics (e.g. carbamazepine and phenytoin)

There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine.

Concomitant use of zalcitabine with isoniazid has been shown to approximately double the renal clearance if isoniazid in HIV infected patients.

Administration of prednisolone 20 mg to 13 slow acetylators and 13 fast acetylators for receiving isoniazid 10 mg/kg reduced plasma concentrations of isoniazid by 25% and 40%, respectively. The clinical significance of this effect has not been established.

The effect of acute alcohol intake (serum levels 1 g/L maintained for 12 hours) on the metabolism of isoniazid (300 mg/d for 2 days) was studies in 10 healthy volunteers in a controlled cross over design. The metabolism of isoniazid and its metabolite, acetyl isoniazid, was not modified by this acute alcohol intake. The metabolism of isoniazid may be increased in chronic alcoholics; however, this effect has not been quantified.

Other Interactions

Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competing for acetylating enzymes.

General anaesthetics may increase the hepatotoxicity of isoniazid.

The absorption of isoniazid is reduced by antacids.

The risk of CNS toxicity is increased when isoniazid is given with cycloserine.

Isoniazid may reduce plasma concentration of ketoconazole and increase plasma concentration of theophylline.

Interactions with pyrazinamide

Pyrazinamide antagonizes the effects of probenecid and sulfinpyrazone.

Food Interaction

Isoniazid is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO), therefore can reduce tyramine and histamine metabolism, causing symptoms such as headache, sweating, palpitations, flushing, and hypotension. Patients should be advised against ingesting foods rich in tyramine and/or histamine during treatment with isoniazid, such as cured meat, some cheeses (e.g. matured cheeses), wine, beer and some fish (e.g. tuna, mackerel, salmon).

4.6. Fertility, pregnancy and lactation

Pregnancy

Rifampicin

At very high doses in animals rifampicin has been shown to have teratogenic effects. There are no well controlled studies with Rifater 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.

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

Isoniazid

It has been reported that in both rats and rabbits, isoniazid may exert an embryocardial effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, rabbits).

Therefore, Rifater 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.

Breast-feeding

Rifampicin, isoniazid and pyrazinamide are excreted in breast milk and infants should not be breast-fed by a patient receiving Rifater unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant.

In breast-fed infants whose mothers are taking isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B6 deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine.

4.7. Effects on ability to drive and use machines

Isoniazid has been associated with vertigo, visual disorders and psychotic reactions (see section 4.8). Patients should be informed of these, and advised that if affected, they should not drive, operate machinery or take part in any activities where these symptoms may put either themselves or others at risk.

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).

Rifampicin

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

Hemolytic anemia

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

Not known

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).

Isoniazid

System organ class

Frequency

Preferred Term

Hepatobiliary disorders

Uncommon

Severe and sometimes fatal hepatitis may occur with isoniazid therapy

Nervous system disorders

Uncommon

Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis.

Not known

Vertigo

Polyneuritis associated with isoniazid, presenting as paraesthesia, muscle weakness, loss of tendon reflexes etc, is unlikely to occur with the recommended daily dose of Rifater. The incidence is higher in “slow acetylators”.

The possibility that the frequency of seizures may be increased in patients with epilepsy should be borne in mind.

Cerebellar syndrome (including cerebellar ataxia, ataxia, dysdiadochokinesis, balance disorders, nystagmus, dysmetria) mainly in patients with chronic kidney disease.

Immune system disorders

Not known

Anaphylactic reactions

Blood and lymphatic system disorders

Not known

Thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uremic syndrome

Eosinophilia

Agranulocytosis

Thrombocytopenia

Anaemia (including aplastic, haemolytic and sideroblastic anaemia)

Skin and subcutaneous tissue disorders

Not known

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome (see section 4.4)

Rash

Acne

Toxic epidermal necrolysis (TEN)

Stevens-Johnson syndrome

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

Exfoliative dermatitis

Pemphigus

Alopecia

Vascular disorders

Not known

Vasculitis

Endocrine disorders

Not known

Gynecomastia

Gastrointestinal disorders

Not known

Constipation

Dry mouth

Nausea

Vomiting

Epigastric distress

Pancreatitis

Metabolism and nutrition disorders

Not known

Hyperglycaemia

Pellagra

Investigations

Not known

Anti-nuclear bodies

General disorders and administration site conditions

Not known

Fever

Musculoskeletal and connective tissue disorders

Not known

Systemic lupus erythromatosus-like syndrome

Pyrazinamide

System organ class

Frequency

Preferred Term

Hepatobiliary disorders

Rare

Acute yellow atrophy

Death

Not known

The hepatic reaction is the most common adverse reaction and varies from a symptomless abnormality of hepatic cell function detected only through laboratory liver function tests, through a mild syndrome of fever, malaise and liver tenderness, to more serious reactions such as clinical jaundice

Musculoskeletal and connective tissue disorders

Not known

Arthralgia

Blood and lymphatic system disorders

Not known

Sideroblastic anaemia

Thrombocytopenia with or without purpura

Metabolism and nutritional disorders

Not known

Active gout (pyrazinamide has been reported to reduce urate excretion)

Anorexia

Gastrointestinal disorders

Not known

Nausea

Vomiting

Aggravation of peptic ulcer

Renal and urinary disorders

Not known

Dysuria

General disorders and administration site conditions

Not known

Malaise

Fever

Skin and subcutaneous tissue disorders

Very Rare

Angioedema

Not known

Stevens-Johnson Syndrome (SJS)

Toxic Epidermal Necrolysis (TEN) (See section 4.4)

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

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome (see section 4.4)

Urticaria

Pruritus

Erythema

Rash

Photosensitivity reaction

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

There is limited overdose information involving rifampicin, isoniazid and pyrazinamide in combination.

Signs and Symptoms

Rifampicin

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 paediatrics patients ages 1 - 4 years old of 100 mg/kg for one to two doses have been reported.

Isoniazid

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colours and strange designs), are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycaemia are typical laboratory findings.

Pyrazinamide

There is limited information related to pyrazinamide overdose. Liver toxicity and hyperuricemia may occur with overdosage.

Management

In cases of overdosage with Rifater, gastric lavage should be performed as soon as possible. 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.

Intensive supportive measures should be instituted, including airway patency and individual symptoms treated as they arise.

Isoniazid

If acute isoniazid overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B6) should be considered. In patients with seizures not controlled with pyridoxine (vitamin B6), anticonvulsant therapy should be administered. Sodium bicarbonate should be given to control metabolic acidosis. Haemodialysis is advised for refractory cases; if this is not available, peritoneal dialysis can be used along with forced diuresis.