Otofa

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

Indications for use

Tuberculosis: In combination with other active anti-tuberculosis drugs in the treatment of all forms of tuberculosis, including fresh, advanced, chronic and drug-resistant cases. Otofa is also effective against most atypical strains of Mycobacteria.

Leprosy: In combination with at least one other active anti-leprosy drug in the management of multibacillary and paucibacillary leprosy to effect conversion of the infectious state to a non-infectious state.

Other Infections: In the treatment of Brucellosis, Legionnaires Disease, and serious staphylococcal infections. To prevent emergence of resistant strains of the infecting organisms, Otofa should be used in combination with another antibiotic appropriate for the infection.

Prophylaxis of meningococcal meningitis: For the treatment of asymptomatic carriers of N. meningitidis to eliminate meningococci from the nasopharynx.

Haemophilus influenzae: For the treatment of asymptomatic carriers of H.influenzae and as chemoprophylaxis of exposed children, 4 years of age or younger.

Posology

Tuberculosis

Otofa should be given with other effective anti-tuberculosis drugs to prevent the possible emergence of Otofa 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

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

Adults: 600mg of Otofa 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:

Otofa 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 Otofa is 450 mg once a month.

For children less than 10 years, the recommended dose for Otofa is 10 to 20 mg/kg Otofa 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 Otofa 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 Otofa in elderly patients, caution should be exercised in using Otofa in such patients, especially if there is evidence of liver function impairment.

Method of Administration

For oral administration only.

The daily dose of Otofa, 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.

Recommended Dosage

For oral administration

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

Tuberculosis:

Otofa 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 8-12 mg/kg.

Usual Daily dose: Patients weighing less than 50 kg - 450 mg. Patients weighing 50 kg or more - 600 mg.

Children: 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.

Leprosy:

600 mg doses of rifampicin should be given once per month. Alternatively, a daily regimen may be used. The recommended single 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.

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 600-1200 mg given in 2 to 4 divided doses, together with another appropriate antibiotic to prevent the emergence of resistant strains of the infecting organisms.

Prophylaxis of meningococcal meningitis

Adults: 600 mg twice daily for 2 days.

Children (1 - 12 years): 10 mg/kg twice daily for 2 days.

Children (3 months - 1 year): 5 mg/kg twice daily for 2 days.

Prophylaxis of Haemophilus influenzae

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

Index cases should be treated prior to discharge from hospital.

Neonates (1 month): 10 mg/kg daily for 4 days.

Impaired liver function:

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

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

Otofa is contra-indicated in the presence of jaundice, and in patients who are hypersensitive to the rifamycins or any of the excipients.

Otofa use is contraindicated when given concurrently with the combination of saquinavir/ritonavir.

Otofa 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 Otofa 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 Otofa in cases of necessity, and then with caution and under close medical supervision. In these patients, lower doses of Otofa 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, Otofa should be withdrawn.

Otofa 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 Otofa 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 Otofa. 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 Otofa 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.

Otofa 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 Otofa 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.

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

Otofa 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.

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 Otofa. 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 occurring with intermittent therapy (less than 2 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment.

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.

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.

Otofa Oral Suspension should be discontinued if an alternative etiology for the signs and symptoms cannot be established.

Otofa Oral Suspension contains sodium metabisulfite which may cause allergic type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people.

The suspension contains 2 g of sucrose per 5 ml dose. This should be taken into account in patients with diabetes mellitus. This may also be harmful to teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Otofa Oral Suspension contains 7.2mg of sodium (0.24mg/ml) per 600 mg daily dose and is essentially 'sodium-free'.

Otofa Oral Suspension contains Methyl-p-hydroxybenozoate and propyl-p-hydroxybenzoate, these may cause allergic reactions (possibly delayed).

This medicine contains potassium, less than 1 mmol (10.4mg) per 30ml dose, i.e. is essentially 'potassium free'.

Otofa Oral Suspension may produce 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.

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

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

None stated

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 Otofa therapy.

Hepatobiliary disorders

Hepatitis can be caused by Otofa 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 Otofa 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 Otofa.

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 Otofa.

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 Otofa 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, Otofa 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 Otofa.

Otofa 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.

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).

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

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 , 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

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 Otofa. 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.

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.

Pharmacotherapeutic group: Antimycobacterials, antibiotics, ATC code: J04AB02

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

Otofa 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 Otofa has only been shown with other rifamycins.

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.

Otofa 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 Otofa 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 Otofa 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.

Otofa is rapidly eliminated in the bile and an enterophepatic circulation ensues. During this process, Otofa 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.

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

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.

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

Not applicable

None known

None stated

No special requirements.

Not applicable