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.
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-Ferein. 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.
Rifampicin is contraindicated in patients who:
- are hypersensitive to any of the rifamycins or to any of the excipients listed in section 6.1;
- have jaundice;
- are concurrently receiving saquinavir/ritonavir therapy (see section 4.5 Interactions with other medicinal products and other forms of interaction).
Rifampicin-Ferein is contraindicated when given concurrently with the combination of saquinavir/ ritonavir.
None known.
None known
| Frequency estimates: | Common: Uncommon: Rare: Very rare: Unknown | > 1/100 > 1/1,000 to ≤ 1/100 > 1/10,000 to ≤ 1/1,000 < 1/10,000 Cannot be estimated from available data |
Reactions occurring with either daily or intermittent dosage regimens include:
| System Organ Class | Common | Uncommon | Unknown |
| Infections and infestations | Pseudomembranous colitis, influenza consisting of episodes of pyrexia, chills, headache, dizziness | ||
| Blood and lymphatic system disorders | Thrombocytopenia with or without purpura, usually associated with intermittent therapy, but is reversible if drug is discontinued as soon as purpura occurs. | leukopenia | Disseminated intravascular coagulation,eosinophilia, agranulocytosis, hemolytic anemia |
| Immune system disorders | anaphylactic reaction | ||
| Endocrine disorders | adrenal insufficiency in patients with compromised adrenal function have been observed. | ||
| Metabolism and nutritional disorders | decreased appetite | ||
| Psychiatric disorders | Psychotic disorder | ||
| Nervous system disorders | Cerebral hemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura. | ||
| Eye disorders | Tear discoloration | ||
| Vascular disorders | Shock, flushing, vasculitis | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea, wheezing, sputum discoloured | ||
| Gastrointestinal disorders | Nausea, vomiting | Diarrhea | Gastrointestinal disorder, abdominal discomfort |
| Hepatobiliary disorders | Hepatitis, hyperbilirubinaemia | ||
| Skin and subcutaneous tissue disorders | Erythema multiforme including Stevens-Johnson syndrome and toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome , skin reaction, pruritus, rash pruritic, urticaria, dermatitis allergic, pemphigoid, sweat discoloration. | ||
| Musculoskeletal and connective tissue disorders | Muscle weakness, myopathy, bone pain | ||
| Renal and urinary disorders | acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia | ||
| Pregnancy, puerperium and perinatal conditions | Post-partum haemorrhage, fetal-maternal haemorrhage | ||
| Reproductive system and breast disorders | Menstrual disorder | ||
| Congenital, familial and genetic disorders | Porphyria | ||
| General disorders and administration site conditions | Edema | ||
| Investigations | Blood bilirubin increased, aspartate aminotransferase increased, alanine aminotransferase increased | Blood pressure decreased, blood creatinine increased, hepatic enzyme increased |
| System Organ Class | Common | Uncommon | Rare | Very rare |
Reactions usually occurring with intermittent dosage regimens and probably of immunological origin include:
- 'Flu Syndrome' consisting of episodes of fever, chills, headache, dizziness, and bone pain appearing most commonly during the 3rd to the 6th monthly of therapy. The frequency of the syndrome varies but may occur in up to 50 % of patients given once-weekly regimens with a dose of rifampicin of 25 mg/kg or more.
- Shortness of breath and wheezing.
- Decrease in blood pressure and shock.
- Anaphylaxis.
- Acute haemolytic anaemia.
- Acute renal failure usually due to acute tubular necrosis or acute interstitial nephritis.
If serious complications arise, e.g. renal failure, thrombocytopenia or haemolytic anaemia, rifampicin should be stopped and never restarted.
Rifampicin may produce a reddish colouration of the urine, sweat, sputum and tears. The patient should be forewarned of this. Soft contact lenses may be permanently stained.
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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.
Reactions occurring with either daily or intermittent dosage regiments include:
Skin and subcutaneous tissue disorders
Cutaneous reactions which are mild and self-limiting may occur and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. Urticaria and more serious hypersensitivity cutaneous reactions have occurred but are uncommon. Exfoliate dermatitis, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, Lyells syndrome and vasculitis have been reported rarely.
Gastrointestinal disorders
Gastrointestinal reactions consist of anorexia, nausea, vomiting, abdominal discomfort, and diarrhoea. Pseudomembranous colitis has been reported with Rifampicin-Ferein therapy.
Hepatobiliary disorders
Hepatitis can be caused by Rifampicin-Ferein and liver function tests should be monitored.
Nervous system disorders
Central Nervous system: Psychoses have been rarely reported.
Vascular disorders
Thrombocytopenia with or without purpura may occur, usually associated with intermittent therapy, but is reversible if drug is discontinued as soon as purpura occurs. Cerebral haemorrhage and fatalities have been reported when Rifampicin-Ferein administration has been continued or resumed after the appearance of purpura.
Disseminated intravascular coagulation has also been rarely reported.
Blood and lymphatic system disorders
Eosinophilia, leucopenia, oedema have been reported to occur in a small percentage of patients treated with Rifampicin-Ferein.
Agranulocytosis has been very rarely reported.
Endocrine disorders
Rare reports of adrenal insufficiency in patient with compromised adrenal function have been observed.
Musculoskeletal and connective tissue disorders
Muscle weakness and myopathy have been reported to occur in a small percentage of patients treated with Rifampicin-Ferein.
Immune system disorders
Reactions usually occurring with intermittent dosage regimens and most probably of immunological origin include:
- 'Flu Syndrome' consisting of episodes of fever, chills, headache, dizziness, and bone pain appearing most commonly during the 3rd to the 6th month of therapy. The frequency of the syndrome varies but may occur in up to 50% of patients given once-weekly regimens with a dose of Rifampicin-Ferein of 25mg/kg or more.
- Shortness of breath and wheezing
- Decrease in blood pressure and shock
- Anaphylaxis
- Acute haemolytic anaemia
- Acute renal failure usually due to acute tubular necrosis or to acute interstitial nephritis.
General disorders and administration site conditions
If serious complications arise, e.g. renal failure, thrombocytopenia or haemolytic anaemia, Rifampicin-Ferein should be stopped and never restarted.
Occasional disturbances of the menstrual cycle have been reported in women receiving long term anti-tuberculosis therapy with regimens containing Rifampicin-Ferein.
Rifampicin-Ferein may produce a reddish discolouration of the urine, sweat, sputum and tears. The patient should be forewarned of this. Soft contact lenses may be permanently stained.
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 internet at www.mhra.gov.uk/yellowcard.
There is limited evidence as to the carcinogenic potential of rifampicin in animals. In female mice of a strain known to be susceptible to hepatomas, a significant increase in such tumours was observed after 1 year of treatment with rifampicin in quantities equivalent to 2-10 times the maximum clinical doses.
In mice of another strain treated for 1 year, and in rats treated for 2 years, no significant increase was noted in the incidence of any type of tumour. Studies with various mammalian models, as well as with bacteria, yielded no evidence that rifampicin has a mutagenic effect.
In daily doses of 150-250 mg/kg, rifampicin proved teratogenic in mice and rats, insofar as an increased occurrence of spina bifida and cleft palate was observed. In rabbits it had no teratogenic effect. In all three animal species, unspecific embryotoxic effects occurred after doses > 150 mg/kg.
There are no preclinical safety data of relevance to the prescriber which are additional to those already included in other sections of the SPC.
Rifampicin is a major drug in the management of tuberculosis (all forms) and certain opportunistic mycobacterial infections. It is effective in cases resistant to other anti-tuberculosis agents and shows no cross-resistance outside the rifampycin group of drugs. In the treatment of tuberculosis Rifampicin must always be combined with other anti-tuberculosis agents. It is effective in combination with isoniazid, streptomycin, pyrazinamide, ethambutol and the majority of second line drugs.
Prophylaxis of meningococcal meningitis in close contact adult and paediatric patients
Tuberculosis: Rifampicin-Ferein, 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-Ferein 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-Ferein 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-Ferein is indicated in the treatment of brucellosis, legionnaires disease, and serious staphylococcal infections. Rifampicin-Ferein should be used in combination with another appropriate antibiotic to prevent emergence of resistant strains of the infecting organism.
Pharmacotherapeutic group: Antimycobacterials, antibiotic.
ATC code: J04AB02.
Mechanism of action
Rifampicin exerts, both in vitro and in vivo bactericidal effects on Mycobacterium tuberculosis. It also exhibits variable activity against other atypical species of Mycobacterium.
In vivo it exerts its bactericidal effect not only on micro-organisms in the extracellular spaces but also on those located intracellularly. Rifampicin has a potent sterilising effect.
Rifampicin inhibits the DNA-dependent RNA polymerase of sensitive bacterial strains, but without affecting the corresponding mammalian enzyme.
Since relatively rapid "one-step" selection of resistant bacteria occurs with rifampicin, the drug must not be employed as monotherapy to treat overt infections. Bacteria resistant to rifampicin display no cross-resistance to other antibiotics with the exception of the rifamycins.
Pharmacotherapeutic group: Antimycobacterials, antibiotics, ATC code: J04AB02
Rifampicin-Ferein is an active bactericidial antituberculosis drug which is particularly active against the rapidly growing extracellular organisms and also has bactericidial activity intracellularly. Rifampicin-Ferein has activity against slow and intermittently-growing M Tuberculosis.
Rifampicin-Ferein 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-Ferein has only been shown with other rifamycins.
Absorption
Rifampicin is rapidly and completely absorbed. Following a single dose taken on an empty stomach (600 mg) the peak serum concentrations (approx. 10 µg/ml) are observed after about 2 hours. Ingestion with food may adversely affect the absorption of rifampicin.
Distribution
The apparent distribution volume is 1.6 L/kg in adults and 1.1 L/kg in children. Binding to serum proteins amounts to 84%-91%.
Rifampicin penetrates rapidly into various body fluids and tissues, including bone tissue. Rifampicin crosses the blood/brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for Mycobacterium tuberculosis for up to two months with continuous therapy of 600 mg/day orally.
Rifampicin crosses the human placenta and is secreted in human breast milk. However, it is estimated that a breast-fed infant would receive no more than 1% of the usual therapeutic dose.
Biotransformation
Rifampicin is metabolised in the liver, the principal metabolite being 25-O-deacetylrifampicin, which is microbiologically active and, like rifampicin, subject to enterohepatic circulation. Rifampicin induces its own metabolism.
Elimination
The plasma elimination half-life of rifampicin increases with increasing doses and amounts to 2.5h, 3-4h and about 5h after single doses of 300 mg, 600 mg and 900 mg respectively. After a few days of repeated daily administration, the bioavailability of rifampicin diminishes, and the half-life value following repeated doses of 600 mg falls to 1-2 hours.
Owing to its enzyme-inducing effect in the liver, rifampicin accelerates its own metabolism, with the result that its systemic clearance, which amounts to approx. 6 L/h after the first dose, rises to approx. 9 L/h after repeated dosing.
Although the bulk of the drug is eliminated in the bile, 80% of the quantity excreted being accounted for by the deacetylrifampicin metabolite, rifampicin also appears in the urine. In a dosage range of 150-900 mg, 4-18% of a dose is excreted dose-dependently in the urine in unchanged form.
Characteristics in patients
In elderly patients, renal clearance is reduced, but, owing to the large scale on which the drug is eliminated via the liver, the plasma concentrations are similar to those in young patients.
With impaired renal function, the elimination half-life becomes prolonged only at doses exceeding 600 mg daily. Provided that hepatic excretory function is normal, the dosage in patients with impaired renal function does not need to be reduced below 600 mg daily. Rifampicin is eliminated by peritoneal or haemodialysis. Dosage adjustment is not necessary during dialysis. Because rifampicin is dialysable it is recommended that the drug should not be administered until after the period of dialysis is complete.
In patients with severe hepatic dysfunction the dosage may have to be adjusted as plasma concentrations are raised and half-life prolonged.
Rifampicin-Ferein 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-Ferein 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-Ferein 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-Ferein is rapidly eliminated in the bile and an enterophepatic circulation ensues. During this process, Rifampicin-Ferein 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-Ferein is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin-Ferein is about 80 % protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.
In the treatment of tuberculosis 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 pretreatment measurement 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 be withdrawn if clinically significant changes in hepatic function occur. The need for other forms of antituberculous therapy and a different regimen should be considered. Urgent advice should be obtained from a specialist in the management of tuberculosis. If rifampicin is reintroduced after liver function has returned to normal, liver function should be monitored daily.
In patients with or likely to have liver function abnormalities including those with chronic liver disease, chronic alcoholism, elderly patients, malnourished patients, and possibly, children under two years of age, the benefit of combined treatment with rifampicin must be weighed against the possible risks. This applies particularly to combination of isoniazid and/or pyrazinamide with rifampicin. In the presence of severely impaired liver function or jaundice the dosage may have to be reduced. If a patient has no evidence of pre-existing liver disease and normal pretreatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient's condition occurs.
Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions.
As rifampicin is excreted principally by the biliary tract, caution should be exercised in treating patients with hepatic disorders.
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.
Patients receiving Rifampicin for the chemoprophylaxis of meningococcal meningitis should be kept under close surveillance. Special attention should be paid to signs of overt infection.
Rifampicin should not be used to treat an overt meningococcal infection.
To prevent the emergence of resistant bacteria, Rifampicin must always be combined with other antibiotics/chemotherapeutic agents when used to treat infections.
Intermittent therapy
The "flu syndrome" is chiefly encountered during intermittent therapy and may be a prelude to serious complications such as thrombocytopenia, purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock and renal failure. In the event of its onset, therefore, one should consider the possibility of switching to daily medication. Such a switch must always be made where the "flu syndrome" assumes a relatively severe form and if the aforementioned serious complications occur, the medication must be withdrawn at once and never reinstituted.
Because of the possibility of immunological reaction including anaphylaxis occurring with intermittent therapy (less than 2 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment.
When changing over from intermittent to daily therapy, an incremental dosage must be employed, starting with approx. 75-150 mg on the first day. The desired therapeutic dose should be reached within 3-4 days. During this time the patient's renal function should be closely monitored. Corticosteroids may prove useful in attenuating possible immunopathological reactions.
Resumption of therapy after its interruption: Since severe reactions such as shock and renal failure may occur in rare cases upon resumption of therapy, incremental dosing under close surveillance is mandatory (see "intermittent therapy").
Owing to its enzyme-inducing effect, rifampicin must be employed with extreme caution in patients with porphyria, because activation of delta-aminolaevulinic acid synthetase may lead to an acute manifestation of the porphyria. Rifampicin can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D.
To preclude all possibility of pregnancy during treatment with Rifampicin, non-hormonal means of contraception must be employed (see section 4.5 Interaction with other medicinal products and other forms of interactions).
Patients should abstain from alcohol while receiving treatment with Rifampicin.
Rifampicin capsules may produce a reddish coloration of the urine, sweat, sputum and tears, and the patient should be forewarned of this. Soft contact lenses have been permanently stained.
All patients with abnormalities should have follow up examinations, including laboratory testing, if necessary.
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.
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.
Rifampicin-Ferein 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-Ferein 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-Ferein in cases of necessity, and then with caution and under close medical supervision. In these patients, lower doses of Rifampicin-Ferein 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-Ferein should be withdrawn.
Rifampicin-Ferein 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-Ferein 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-Ferein. 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-Ferein 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 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-Ferein 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-Ferein 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.
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.
Rifampicin-Ferein capsules should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Rifampicin-Ferein capsules may produce a reddish coloration of the urine, sweat, sputum and tears, and the patient should be forewarned of this. Soft contact lenses have been permanently stained.
All patients with abnormalities should have follow up examinations, including laboratory testing, if necessary.
Contains Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No studies on the effects on the ability to drive and use machines have been performed.
For the management of tuberculosis and certain opportunistic mycobacterial infections:
Rifampicin must always be given in association with other anti-tuberculosis drugs, to prevent emergence of resistant strains.
Use in Adults: 450-600mg daily as a single dose (based on approximately 10mg per kg body weight). (Those patients 50kg (8 stone) and over should take 600mg rifampicin daily, whilst patients under 50kg should take 450mg).
The following chemotherapeutic agents are employed today as combined therapy for tuberculosis: rifampicin (Rifampicin-Fereine) (RMP), isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB), streptomycin (STM).
The dosages recommended by the Centres for Disease Control and Prevention are as follows:
|
| Daily | Twice a week | 3 times a week | ||||||
| Drug | mg/kg | max. mg | mg/kg | max. mg | mg/kg | max. mg | |||
| Children | Adults | Children | Adults | Children | Adults | ||||
| RMP | 10-20 | 10 | 600 | 10-20 | 10 | 600 | 10-20 | 10 | 600 |
| INH | 10-15 | 5 | 300 | 20-40 | 15 | 900 | 20-40 | 15 | 900 |
| PZA | 30-40 | 15-30 | 2,000 | 50-70 | 50-70 | 4,000 | 50-70 | 50-70 | 3,000 |
| EMB | 15-25 | 5-25 | 2,500 | 50 | 50 | 2,500 | 25-30 | 25-30 | 2,500 |
| STM | 20-30 | 15 | 1,000 | 25-30 | 25-30 | 1,500 | 25-30 | 25-30 | 1,000 |
For the treatment of sputum-positive pulmonary tuberculosis, preference is
given to the following regimens: (For dosage information please refer to the text above for Rifampicin and to the table for other components of the treatment).
Continuous therapy
Daily for a total of 9 months
| Initial phase for 2 months: | RMP + INH + PZA + EMB or STM |
| Continuation phase for 7 months: | RMP + INH |
A total duration of 9 months is recommended for tuberculosis with HIV infection and for tuberculous meningitis, disseminated tuberculosis, or spinal involvement with neurological complications.
Daily for a total of 6 months:
| Initial phase for 2 months: | RMP + INH + PZA + EMB or STM |
| Continuation phase for 4 months: | RMP + INH |
Partially intermittent therapy
Total duration 6 months:
| Initial phase for 2 months: | RMP + INH + PZA + EMB or STM daily |
| Continuation phase for 4 months: | RMP + INH twice or 3 times a week |
Fully intermittent therapy
| Total duration 6 months: | RMP + INH + PZA + EMB or STM 3 times a week |
DOTS strategy (directly observed treatment, short-course, i.e. administration of the antituberculous agents under supervision) should be considered for all patients, irrespective of the treatment regimen they are receiving.
Use in Children: Oral doses of 10-20 mg/kg body weight daily are recommended, although a total daily dose should not usually exceed 600 mg.
Use in Elderly: No special dosage regime is necessary but concurrent hepatic insufficiency should be taken into account (see Pharmacokinetics).
For the chemoprophylaxis of meningococcal meningitis:
Note: Rifampicin should not be used to treat overt meningococcal meningitis.
Use in Adults: 600mg twice daily (12 hourly) for 2 days.
Children over 1 month: 10 mg per kg every 12 hours for 2 days
Children under 1 month: 5 mg per kg every 12 hours for 2 days
The maximum dose is 600 mg
Use in the Elderly: There is no evidence to suggest that dose adjustments are necessary.
This prophylactic administration should be started as soon as possible. It is recommended that Rifampicin is only given for 2 days in this indication since resistance to this class of antibacterial agent may develop.
Posology
Tuberculosis
Rifampicin-Ferein should be given with other effective anti-tuberculosis drugs to prevent the possible emergence of Rifampicin-Ferein 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-Ferein should always be used in conjunction with at least one other anti-leprosy drug to treat the disease.
Adults: 600mg of Rifampicin-Ferein 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-Ferein 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-Ferein is 450 mg once a month.
For children less than 10 years, the recommended dose for Rifampicin-Ferein is 10 to 20 mg/kg Rifampicin-Ferein 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-Ferein 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-Ferein in elderly patients, caution should be exercised in using Rifampicin-Ferein in such patients, especially if there is evidence of liver function impairment.
Method of Administration
For oral administration only.
The daily dose of Rifampicin-Ferein, 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.
No special requirements.
