This information is intended for use by health professionals

1. Name of the medicinal product

Rifadin for Infusion 600mg

2. Qualitative and quantitative composition

Rifampicin BP 600mg

3. Pharmaceutical form

Lyophilisate (for reconstitution prior to use) and accompanying ampoule of solvent.

4. Clinical particulars
4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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

Tuberculosis:

Adults: A single daily administration of 600mg given by intravenous infusion over 2 to 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 600mg by mouth.

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

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 antileprosy drug.

Brucellosis, Legionnaires Disease or serious staphylococcal infections:

Adults: The recommended daily dose is 600 - 1200mg given in 2 to 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).

4.3 Contraindications

Rifadin for Infusion is contraindicated in patients who are hypersensitive to rifamycins or any of the excipients.

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

Rifadin for Infusion use is contraindicated when given concurrently with the combination of saquinavir/ritonavir (see section 4.5 Interactions).

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.

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.

Because of the possibility of immunological reaction including anaphylaxis (see section 4.8 Undesirable effects) 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.

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 etiology for the signs and symptoms cannot be established.

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).

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

4.5 Interaction with other medicinal products and other forms of interaction

Cytochrome P-450 enzyme interaction

Rifampicin is a potent inducer of certain cytochrome P-450 enzymes. Coadministration of rifampicin with other drugs that are also metabolised through these cytochrome P-450 enzymes may accelerate the metabolism and reduce the activity of these other drugs. Therefore, caution should be used when prescribing rifampicin 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 concomitantly administered rifampicin.

Examples of drugs metabolised by cytochrome P-450 enzymes are:

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

• Antiepileptics (e.g. phenytoin),

• Hormone antagonist (antiestrogens e.g. tamoxifen, toremifene, gestinone),

• Antipsychotics (e.g. haloperidol, aripiprazole),

• Anticoagulants (e.g. coumarins),

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

• 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, zolpicolone, 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,

• Systemic hormonal contraceptives

• Oestrogen,

• Antidiabetic (e.g. chlorpropamide, tolbutamide, sulfonylureas, rosiglitazone),

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

• Irinotecan,

• Thyroid hormone (e.g. levothyroxine),

• Losartan,

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

• Praziquantel,

• Progestogens,

• 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)

Patients on oral contraceptives should be advised to use alternative, non-hormonal methods of birth control during Rifadin therapy. Also diabetes may become more difficult to control.

Other Interactions

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

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

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

Concurrent use of rifampicin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.

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.

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.

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.

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.

4.6 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 foetus 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.

Lactation

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.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable:

Very common ≥ 10 %; Common ≥ 1 and <10%; Uncommon ≥ 0.1 and <1%; Rare ≥ 0.01 and <0.1%; Very rare <0.01%, Unknown (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:

Infections and infestations

Unknown: 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

Unknown: Disseminated intravascular coagulation,eosinophilia, agranulocytosis, hemolytic anemia

Immune system disorders

Unknown: anaphylactic reaction

Endocrine disorders

Unknown: adrenal insufficiency in patients with compromised adrenal function have been observed.

Metabolism and nutritional disorders

Unknown: decreased appetite

Psychiatric disorders

Unknown: Psychotic disorder

Nervous system disorders

Common: headache, dizziness

Unknown: Cerebral hemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura.

Eye disorders

Unknown: Tear discoloration

Vascular disorders

Unknown: Shock, flushing, vasculitis

Respiratory, thoracic and mediastinal disorders

Unknown: Dyspnoea, wheezing, sputum discoloured

Gastrointestinal disorders

Common: Nausea, vomiting

Uncommon: Diarrhea

Unknown: Gastrointestinal disorder, abdominal discomfort, tooth discoloration (which may be permanent)

Hepatobiliary disorders

Unknown: Hepatitis, hyperbilirubinaemia (see section 4.4: Special warnings and precautions for use)

Skin and subcutaneous tissue disorders

Unknown: Erythema multiforme including Stevens-Johnson syndrome and toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome (See section 4.4), skin reaction, pruritus, rash pruritic, urticaria, dermatitis allergic, pemphigoid, sweat discoloration.

Musculoskeletal and connective tissue disorders

Unknown: Muscle weakness, myopathy, bone pain

Renal and urinary disorders

Unknown: acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia

Pregnancy, puerperium and perinatal conditions

Unknown: Post-partum haemorrhage, fetal-maternal haemorrhage

Reproductive system and breast disorders

Unknown: Menstrual disorder

Congenital, familial and genetic disorders

Unknown: Porphyria

General disorders and administration site conditions

Very common: Pyrexia, chills

Unknown: Edema

Investigations

Common: Blood bilirubin increased, aspartate aminotransferase increased, alanine aminotransferase increased

Unknown: Blood pressure decreased, blood creatinine increased, hepatic enzyme increased

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

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 to 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 to 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Rifampicin is an active bactericidial antituberculosis drug which is particularly active against the rapidly growing extracellular organisms and also has bactericidial 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.

5.2 Pharmacokinetic properties

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 µg/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.

5.3 Preclinical safety data

Not applicable

6. Pharmaceutical particulars
6.1 List of excipients

Sodium sulfoxylate formaldehyde

Sodium hydroxide

Solvent

Water for Injections.

6.2 Incompatibilities

Compatibilities: Rifadin for Infusion is compatible with the following infusion solutions: up to 6 hours with Saline Solution and up to 8 hours with Glucose 5%.

Incompatibilities: Rifadin for Infusion is incompatible with the following: Perfudex, Sodium Bicarbonate 5%, Sodium Lactate 0.167M, Ringer Acetate with Glucose.

6.3 Shelf life

Unopened vial of lyophilisate:

Unopened ampoule of solvent:

36 months

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

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Aventis Pharma Limited

Trading as Marion Merrell or Aventis Pharma

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Or trading as

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing authorisation number(s)

PL 04425/0051

9. Date of first authorisation/renewal of the authorisation

7th December 1982 / 9th April 2005

10. Date of revision of the text

22nd March 2018

LEGAL STATUS

POM