Rifadin for Infusion is indicated for acutely ill patients who are unable to tolerate oral therapy, e.g. post-operative or comatose patients or patients in whom gastrointestinal absorption is impaired.

Tuberculosis:

Rifadin, used in combination with other active anti-tuberculosis drugs, is indicated 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:

Rifadin, used in combination with at least one other active anti-leprosy drug, is indicated in the management of multibacillary and paucibacillary leprosy to effect conversion of the infectious state to a non-infectious state.

Other infections:

Rifadin is indicated 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.

Posology

Treatment with Rifadin for Infusion should include concomitant use of other appropriate anti-bacterials to prevent the emergence of resistant strains of the causative organism.

Tuberculosis

Adults: A single daily administration of 600 mg given by intravenous infusion over 2 - 3 hours has been found to be effective and well tolerated for adult patients. Serum concentrations following this dosage regimen are similar to those obtained after 600 mg by mouth.

Children: The usual paediatric regimen is a single daily dose of up to 20 mg/kg bodyweight; the total daily dose should not normally exceed 600 mg.

Leprosy

The recommended 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

Alternatively, 600 mg doses of rifampicin may be given once per month.

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 antibacterial agent with similar properties to prevent the emergence of resistant strains.

Impaired liver function

A daily dose of 8mg/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 serum terminal half-life 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 liver function impairment.

When patients are able to accept oral medication, they should be transferred to Rifadin Capsules or Syrup (for further information on these products see their separate data sheets).

Rifadin for Infusion is contraindicated in:

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

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

Although not recommended for use in patients with jaundice, the therapeutic benefit of Rifadin for Infusion should be weighed against the possible risks.

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.

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 rifampicin. 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 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment 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.

Cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS), including fatal cases, have been reported with Rifadin Infusion use. If laboratory or clinical findings associated with TMA occur in a patient receiving Rifadin Infusion, 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 Infusion 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 infusion should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

After initial improvement of tuberculosis under therapy with Rifadin infusion, 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 Infusion 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 Infusion 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 infusion is for intravenous infusion only and must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection; local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.

Rifadin infusion 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 infusion 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, hypoprothrombinaemia).

There have been reports of interstitial lung disease (ILD) or pneumonitis in patients receiving Rifadin Infusion 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 Infusion should be permanently discontinued in case of severe manifestations (respiratory failure and acute respiratory distress syndrome) and appropriate treatment initiated as necessary.

Excipients

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

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 daily administration of Rifadin for Infusion.

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 Infusion on other medicinal products

Induction of Drug Metabolizing Enzymes and Transporters

Rifadin infusion is a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifadin infusion 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 infusion simultaneously. Therefore, Rifadin infusion 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. To maintain optimum therapeutic blood levels, dosages of drugs may require adjustment when starting or stopping concomitantly administered Rifadin infusion.

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, 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)

• Antibacterials (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)

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 hepatitis-C antiviral drugs and rifampicin should be avoided.

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. 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): Concurrent use of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs.

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 infusion

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 infusion

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

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 for Infusion 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 and infants should not be breast-fed by a patient receiving rifampicin unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant.

None known.

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).

Rifadin for Infusion is generally well tolerated and accepted by patients, although hypersensitivity reactions have been described and occasionally patients have experienced fever, skin rashes and nausea/vomiting.

Occasional instances of phlebitis and pain at the infusion site have been reported.

Reactions occurring with either daily or intermittent dosage regimens include:

*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.

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.

Pharmacotherapeutic group: Anti-mycobacterials, antibiotics, ATC Code: J04AB02.

Rifampicin is an active bactericidial antituberculosis drug which is particularly active against the rapidly growing extracellular organisms and also has bactericidal activity intracellularly. Rifampicin has activity against slow and intermittently-growing M. Tuberculosis.

Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Cross-resistance to rifampicin has only been shown with other rifamycins.

After intravenous administration of a 300 or 600 mg dose of Rifadin infusion infused over 30 minutes to healthy male volunteers (n = 12), mean peak plasma concentrations were 9.0 and 17.5 µ g/ml, respectively. The average plasma concentrations in these volunteers remained detectable for 8 and 12 hours, respectively.

The pharmacokinetics (oral and intravenous) in children are similar to adults.

In normal subjects the biological half-life of rifampicin in serum averages about 3 hours after a 600 mg dose and increases to 5.1 hours after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 – 3 hours. At a dose of up to 600 mg/day, it does not differ in patients with renal failure and consequently, no dosage adjustment is required.

Rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, rifampicin undergoes progressive deacetylation, so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite retains essentially complete antibacterial activity. Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Up to 30% of a dose is excreted in the urine, with about half of this being unchanged drug.

Rifampicin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.

Not applicable

Sodium sulfoxylate formaldehyde

Sodium hydroxide

Solvent

Water for Injections

Compatibilities: up to 6 hours with Saline Solution and up to 8 hours with Glucose 5%.

Incompatibilities: Perfudex, Sodium Bicarbonate 5%, Sodium Lactate 0.167M, Ringer Acetate with Glucose.

Unopened vial of lyophilisate: 36 months

Unopened ampoule of solvent: 60 months

Shelf life after dilution or reconstitution:

Water for Injections (10 ml WFI): Up to 30 hours

Water for injections (10 ml WFI) and then diluted in glucose 5% solution for infusion: Up to 8 hours

Water for injections (10 ml WFI) and then diluted in sodium chloride 0.9% solution for infusion: Up to 6 hours

Store below 25^oC.

20ml clear neutral glass vial sealed with butyl rubber stopper and aluminium/plastic “ flip-off” cap (colour coded blue) containing 600mg Rifampicin and 10ml clear glass ampoule containing solvent.

Pack size: combination of 1 vial of lyophilisate and 1 ampoule of solvent.

Not applicable.