This information is intended for use by health professionals

1. Name of the medicinal product

Rifampicin 300 mg Capsules

2. Qualitative and quantitative composition

Each capsule contains 300 mg rifampicin.

Excipients with known effect:

Each capsule contains 31 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsule, hard

Size no.1 hard gelatin capsules with a pink body and maroon cap, marked “RN 300” and “G”. (The capsule contents are brick red).

4. Clinical particulars
4.1 Therapeutic indications

Tuberculosis: Rifampicin, 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. Rifampicin is also effective against most atypical strains of mycobacteria.

Prophylaxis of meningococcal meningitis: Prophylaxis of meningococcal meningitis in close contact adult and paediatric patients.

Leprosy: Rifampicin is indicated in the combination treatment of multibacillary and paucibacillary leprosy in patients of all age groups.

Haemophilus influenzae: Propylaxis of Haemophilus influenzae type b disease in close contacts.

Other infections: Rifampicin is indicated in the treatment of brucellosis, legionnaires disease, and serious staphylococcal infections. Rifampicin should be used in combination with another appropriate antibiotic to prevent emergence of resistant strains of the infecting organism.

4.2 Posology and method of administration

Posology

Tuberculosis

Rifampicin 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 8-12mg/kg.

Usual daily dose:

Patients weighing less than 50kg – 450mg

Patients weighing 50kg or more – 600mg

Paediatric patients:

Children above 3 months: Oral doses of 15 (10-20) mg/kg body weight daily are recommended, although a total daily dose should not usually exceed 600mg.

Prophylaxis of Meningococcal Meningitis

Adults: 600mg twice daily for 2 days.

Paediatric patients:

Meningococcal Carriers: Dose must not exceed 600 mg/ dose.

For children ≥1 month of age the recommended dose is 10 mg/kg every 12 hours for 2 days.

For children <1 month of age, the recommended dose is 5 mg/kg every 12 hours for 2 days.

Leprosy

Rifampicin should always be used in conjunction with at least one other anti-leprosy drug to treat the disease.

Adults: 600mg of rifampicin should be given once per month. If a daily dose regime is indicated then the recommended single dose is 10mg/kg. The usual daily dose for patients less than 50kg is 450mg and for patients 50kg or more, the usual daily dose is 600mg.

Paediatric patients:

Rifampicin should always be administered with dapsone in case of paucibacillary forms and with dapsone and clofazimine in case of multibacillary forms.

For children over 10 years, the recommended dose for rifampicin is 450 mg once a month.

For children less than 10 years, the recommended dose for rifampicin is 10 to 20 mg/kg rifampicin once a month.

The duration of treatment is 6 months for paucibacillary and 12 months multibacillary forms.

Prophylaxis of Haemophilus Influenzae

Adults and children ≥1 month of age: For members of a household exposed to H. Influenzae B disease when the household contains a child 4 years old or younger, it is recommended that all members (including the child) receive 20mg/kg once daily (maximum daily dose of 600mg) for 4 days.

Index cases should be treated prior to discharge from hospital.

For children <1 month of age: 10mg/kg once daily for 4 days

Brucellosis, Legionnaires Disease or Serious Staphylococcal Infections

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

Patients with 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.

Method of Administration

For oral administration only.

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

4.3 Contraindications

Rifampicin is contra-indicated in the presence of jaundice, and in patients who are hypersensitive to the active substance, rifampicin or any of the excipients listed in section 6.1.

Rifampicin is contraindicated when given concurrently with the combination of saquinavir/ ritonavir (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.

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 and 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. It is rarely necessary, in the absence of clinical findings, to increase the frequency of performing routine liver function tests in patients with normal pretreatment liver unless fever, vomiting, jaundice or other deterioration in the patients 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 resulting from competition between rifampicin and bilirubin for excretory pathways of the liver at the cell level, can occur in 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.

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 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.

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).

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

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 Rifampicin capsules treatment.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

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.

If signs and symptoms suggestive of these reactions appear, Rifampicin capsules 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.

Rifampicin capsules 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 capsules are a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease concomitant drug exposure 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 coagulation and severe bleeding (see Section 4.8). Monitoring of occurrence of coagulation is recommended for patients at particular bleeding risk. Supplemental vitamin K administration should be considered when appropriate (vitamin K deficiency, hypoprothrombinemia).

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

Contains Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic Interactions

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

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 Rifampicin capsules on other medicinal products

Induction of Drug Metabolizing Enzymes and Transporters

Rifampicin capsules are a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifampicin capsules 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 Rifampicin capsules simultaneously. Therefore, Rifampicin capsules may accelerate the metabolism and reduce the activity of certain co-administered drugs, 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 Rifampicin capsules.

Examples of drugs or drug classes affected by rifampicin:

• 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, 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

• Systemic hormonal contraceptives including estrogens and progestogens,

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

• 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 (eg, daclatasvir, simeprevir, sofosbuvir, telaprevir): Concurrent use of treatment of hepatitis-C antiviral drugs and rifampicin should be avoided.

• Morphine: Plasma concentration 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.

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 rifampicin therapy. Also diabetes may become more difficult to control.

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

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

Effect of other medicinal products on Rifampicin capsules.

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.

Other drug interactions with Rifampicin capsules

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

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.

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 the cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. Therefore, rifampicin 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 rifampicin 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, 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

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable:

Ver 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).

Reactions occurring with either daily or intermittent dosage regiments 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, Vitamin K dependent coagulation disorders

Immune system disorders

Unknown: Anaphylactic reaction

Endocrine disorders

Unknown: Adrenal insufficiency in patient 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 haemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura.

Eye disorders

Unknown: Tear discolouration

Vascular disorders

Unknown: Shock, Flushing, Vasculitis, Bleeding

Respiratory, thoracic and mediastinal disorders

Unknown: Dyspnoea, Wheezing, Sputum discoloured

Gastrointestinal disorders

Common: Nausea, Vomiting

Uncommon: Diarrhoea

Unknown: Gastrointestinal disorder, Abdominal discomfort, Tooth discoloration (which may be permanent)

Hepatobiliary disorders

Unknown: Hepatitis, Hyperbilirubinaemia (see section 4.4)

Skin and subcutaneous tissue disorders

Unknown: Erythema multiforme including Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome (See section 4.4), 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

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 the 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 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

Pharmacotherapeutic group: Antimycobacterials, antibiotics, ATC code: J04AB02

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

Rifampicin is readily absorbed from the gastrointestinal tract. Peak serum concentrations of the order of 10 µg/ml occur about 2 to 4 hours after a dose of 10 mg/kg body weight on an empty stomach.

Absorption of rifampicin is reduced when the drug is ingested with food.

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 enterophepatic 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

There are no preclinical safety data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Each capsule contains:

Ascorbic Acid

Lactose monohydrate

Talc

Magnesium Stearate.

The capsule cap and body contains:

Indigotine (E132)

Titanium Dioxide (E171)

Gelatin

Erythrosine (E127)

Red Iron Oxide (E172)

The capsule printing ink contains:

Shellac

Iron oxide black (E172)

Propylene glycol

Ammonium hydroxide

6.2 Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store in a cool dry place.

6.5 Nature and contents of container

Polypropylene containers with polyethylene cap (with optional polyethylene ullage filler) in packs of 5, 7, 8, 10, 14, 15, 16, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 250 and 500 capsules

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 04569/0087

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 3 July 1986

Date of latest renewal: 5 April 2002

10. Date of revision of the text

03 December 2019