Rifater Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rifater Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
3 PHARMACEUTICAL FORM
Tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Rifater is indicated in the treatment of pulmonary tuberculosis.
4.2. Posology and Method of Administration
Rifater is recommended in the initial intensive phase of the short-course treatment of pulmonary tuberculosis. During this phase, which lasts for 2 months, Rifater should be administered on a daily continuous basis. The concomitant administration of ethambutol or intramuscular streptomycin over the same period of time is advised.
Each Rifater tablet contains isoniazid (INH), pyrazinamide (Z) and rifampicin (RAMP) in such a ratio that the administration of 9-12mg/kg RAMP, 4-5mg/kg INH and 23-30mg/kg Z can be achieved by giving 3 tablets daily to patients weighing less than 40kg, 4 tablets to patients weighing 40-49kg, 5 tablets to patients weighing 50-64kg and 6 tablets to patients weighing 65kg or more.
Rifater should be given as a single dose and preferably on an empty stomach at least 30 minutes before a meal, or 2 hours after a meal to ensure rapid and complete absorption.
Once the initial intensive phase of treatment has been completed treatment can be continued with the combination rifampicin-isoniazid (Rifinah) always on a daily basis.
This regimen, if correctly applied, is 100% effective with very few, if any, relapses. The clinical evidence indicates that these occur generally in the first 6 months after stopping treatment with bacilli fully sensitive to the drugs employed, so that changes in the drugs to be utilised for further treatment are not required. The regimen has been found to be fully effective also in the presence of a bacillary population resistant to isoniazid, to streptomycin or to both drugs.
Children: The ratio of the three drugs in Rifater may not be appropriate in children (eg higher mg/kg doses of INH are usually given in children than in adults). Rifater can be used only in special cases, after careful consideration of the mg/kg dose of each component.
Use in the Elderly: Caution should be exercised in such patients, in view of the possible decrease of the excretory function of the kidney and of the liver.
4.3 Contraindications
Rifater is contra-indicated in patients who are hypersensitive to any one of the components of the combination or any of the excipients. Rifater is contra-indicated in the presence of jaundice.
Rifater use is contraindicated when given concurrently with the combination of saquinavir/ritonavir (see section 4.5 Interactions).
4.4 Special warnings and precautions for use
The precautions for the use of Rifater are the same as those considered when a triple individual administration of rifampicin, isoniazid and pyrazinamide is required. Rifater should only be given under supervision. Each of these drugs has been associated with liver dysfunction.
Rifater should be given under the supervision of a respiratory or other suitably qualified physician.
All tuberculosis patients should have pre-treatment measurements of liver function.
Adults treated for tuberculosis with Rifater should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count and a platelet count (or estimate).
Patients should be seen at least monthly during therapy and should be questioned specifically about symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary.
However, because there is a higher frequency of isoniazid-associated hepatitis among persons older than 35 years of age, a transaminase measurement should be obtained at baseline and at least monthly during therapy in this age group. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease, intravenous drug use and being a black or Hispanic woman.
If the 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 occur.
Patients with impaired liver function should only be given Rifater in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every two to four weeks during therapy.
If signs of hepatocellular damage or clinically significant changes in hepatic function occur, Rifater should be withdrawn. 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 Rifater is reintroduced after liver function has returned to normal, liver function should be monitored daily.
Rifampicin
Cautions should be taken in cases of renal impairment if dose > 600 mg/day.
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.
In some cases, hyperbilirubinaemia resulting from competition between rifampicin and bilirubin for excretory pathways of the liver at the cell level can occur in the 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 Undesirable effects) occurring with intermittent rifampicin therapy (less than 2 or 3 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.
Isoniazid
Use of isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction.
Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Therefore, patients should be monitored for the prodromal symptoms of hepatitis; such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.
Care should be exercised in the treatment of elderly or malnourished patients who may also require Vitamin B6 supplementation with the isoniazid therapy.
Use of isoniazid should be carefully monitored in patients with slow acetylator status, epilepsy, history of psychosis, history of peripheral neuropathy, diabetes, alcohol dependence, HIV infection or porphyria.
Pyrazinamide
Rifater should be used with caution in patients with a history of gout. If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing pyrazinamide (e.g. Rifinah 150 or 300).
The possibility of pyrazinamide having an adverse effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.
4.5 Interaction with other medicinal products and other forms of interaction Food Interaction
Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g. headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g. skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving Rifater.
Interactions with other medicinal products
Cytochrome P-450 enzyme interaction
Rifampicin is known to induce and isoniazid is known to inhibit certain cytochrome P-450 enzymes. In general, the impact of the competing effects of rifampicin and isoniazid on the metabolism of drugs that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing Rifater with drugs metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, dosages of drugs metabolised by these enzymes may require adjustment when starting or stopping Rifater.
Interactions with Rifampicin
• Examples of drugs metabolised by cytochrome P-450 enzymes are:
• Antiarrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide),
• Antiepileptics (e.g. phenytoin),
• Hormone antagonist (antiestrogens e.g. tamoxifen, toremifene, gestinone),
• Antipsychotics (e.g. haloperidol, aripiprazole),
• Anticoagulants (e.g. coumarins),
• Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole),
• Antivirals (e.g. saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine),
• Barbiturates
• Beta-blockers (e.g. bisoprolol, propanolol),
• Anxiolytics and hypnotics (e.g. diazepam, benzodiazepines, 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
• Oestrogen,
• 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,
• Progestogens,
• Quinine,
• Riluzole,
• Selective 5-HT3 receptor antagonists (e.g. ondansetron)
• Statins metabolised by CYP 3A4 (e.g. simvastatin),
• Theophylline,
• Tricyclic antidepressants (e.g. amitriptyline, nortriptyline),
• Cytotoxics (e.g. imatinib),
• Diuretics (e.g. eplerenone)
Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during Rifater therapy. Also diabetes may become more difficult to control.
When rifampicin is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifater with saquinavir/ritonavir is contraindicated (see section 4.3 Contraindications).
Other Interactions
Rifampicin may reduce the effect of ACE inhibitors (e.g. enalapril, imidapril), antiemetics (e.g. aprepitant), antineoplastic agents (e.g. imatinib), diuretics (e.g. eplerenone), drugs used in erectile dysfunction (e.g. tadalafil), oral hypoglycemic agents (e.g. nateglinide, repaglinide) and NSAIDS (e.g. etoricoxib).
When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed.
Concurrent use of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs.
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.
The potential for hepatotoxicity is increased with an anaesthetic.
When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampicin and halothane should be avoided. Patients receiving both rifampicin and isoniazid should be monitored closely for hepatotoxicity.
If p-aminosalicylic acid and rifampicin are both included in the treatment regimen, they should be given not less than eight hours apart to ensure satisfactory blood levels.
Interactions with Isoniazid
The following drugs may interact with isoniazid:
Antiepileptics (e.g. carbamazepine and phenytoin)
There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine.
Concomitant use of zalcitabine with isoniazid has been shown to approximately double the renal clearance if isoniazid in HIV infected patients.
Administration of prednisolone 20mg to 13 slow acetylators and 13 fast acetylators for receiving isoniazid 10mg/kg reduced plasma concentrations of isoniazid by 25% and 40%, respectively. The clinical significance of this effect has not been established.
The effect of acute alcohol intake (serum levels 1g/L maintained for 12 hours) on the metabolism of isoniazid (300mg/d for 2 days) was studies in 10 healthy volunteers in a controlled cross over design. The metabolism of isoniazid and its metabolite, acetyl isoniazid, was not modified by this acute alcohol intake. The metabolism of isoniazid may be increased in chronic alcoholics; however this effect has not been quantified.
Other Interactions
Para-aminosalicylic acid may increase the plasma concentration and elimination halflife of isoniazid by competing for acetylating enzymes.
General anaesthetics may increase the hepatotoxicity of isoniazid.
The absorption of isoniazid is reduced by antacids.
The risk of CNS toxicity is increased when isoniazid is given with cycloserine.
Isoniazid may reduce plasma concentration of ketoconazole and increase plasma concentration of theophylline.
Pyrazinamide
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 Pregnancy and lactation
Pregnancy
Rifampicin
At very high doses in animals rifampicin has been shown to have teratogenic effects. There are no well controlled studies with Rifater in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. When administered during the last few weeks of pregnancy, rifampicin may cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K1 may be indicated.
Isoniazid
It has been reported that in both rats and rabbits, isoniazid may exert an embryocardial effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, rabbits).
Therefore, Rifater should be used in pregnant women or in women of childbearing potential only if the potential benefit justifies the potential risk to the foetus.
Lactation
Rifampicin, isoniazid and pyrazinamide are excreted in breast milk and infants should not be breast fed by a patient receiving Rifater unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant.
In breast-fed infants whose mothers are taking isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B6 deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine.
4.7 Effects on ability to drive and use machines
Isoniazid has been associated with vertigo, visual disorders and psychotic reactions (see section 4.8). Patients should be informed of these, and advised that if affected, they should not drive, operate machinery or take part in any activities where these symptoms may put either themselves or others at risk.
4.8 Undesirable effects
The following CIOMS frequency rating is used, when applicable:
Very common (> 1/10); Common (> 1/100 to < 1/ 10); Uncommon (> 1/1,000 to <1/100); Rare (> 1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from available data).
Rifampicin
Reactions occurring with either daily or intermittent dosage regimens include:
Cutaneous reactions which are mild and self-limiting may appear 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.
Gastro-intestinal reactions consist of anorexia, nausea, vomiting, abdominal discomfort, and diarrhoea. Pseudomembranous colitis has been reported with rifampicin therapy.
Hepatitis can be caused by rifampicin and liver function tests should be monitored. (See section 4.4. Special warnings and precautions for use).
Central Nervous System: Psychoses have been rarely reported.
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 administration has been continued or resumed after the appearance of purpura.
Disseminated intravascular coagulation has also been rarely reported.
Eosinophilia, leucopenia, oedema, muscle weakness and myopathy have been reported to occur in a small percentage of patients treated with rifampicin.
Agranulocytosis has been reported very rarely.
Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.
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 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 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.
If serious complications arise, (renal failure, thrombocytopenia or haemolytic anaemia), Rifater 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.
Rifampicin may produce a reddish colouration of the urine, sputum, sweat and tears. The patient should be forewarned of this. Soft contact lenses may be permanently stained.
Isoniazid
Hepatobiliary disorders: Uncommon, Severe and sometimes fatal hepatitis may occur with isoniazid therapy.
Hypersensitivity reactions including fever and anaphylactic reactions have been reported with isoniazid treatment.
Nervous system disorders include vertigo; polyneuritis associated with isoniazid, presenting as paraesthesia, muscle weakness, loss of tendon reflexes etc, is unlikely to occur with the recommended daily dose of Rifater. Various haematological disturbances have been identified during treatment with isoniazid, including eosinophilia, agranulocytosis, thrombocytopenia and anaemia, aplastic anaemia, haemolytic anaemia. High doses of isoniazid can cause convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis. The possibility that the frequency of seizures may be increased in patients with epilepsy should be borne in mind. Systemic
lupus erythromatosus-like syndrome and pellagra have also been reported with isoniazid therapy.
Skin and subcutaneous tissue disorders: (rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis, pemphigus)
Rare: toxic epidermal necrolysis, eosinophilia systemic symptoms Vascular disorders: not known, vasculitis
Gastrointestinal disorder: constipation, dry mouth, nausea, vomiting, epigastric distress) have been reported. not known : Pancreatitis
Other adverse reactions associated with isoniazid therapy are; hyperglycaemia, gynaecomastia and anti-nuclear antibodies
Pyrazinamide
Adverse reactions, other than hepatic reactions, which have been attributed to pyrazinamide are active gout (pyrazinamide has been reported to reduce urate excretion), sideroblastic anaemia, thrombocytopenia with or without purpura, arthralgia, anorexia, nausea and vomiting, dysuria, malaise, fever and aggravation of peptic ulcer. The hepatic reaction is the most common adverse reaction and varies from a symptomless abnormality of hepatic cell function detected only through laboratory liver function tests, through a mild syndrome of fever, malaise and liver tenderness, to more serious reactions such as clinical jaundice and rare cases of acute yellow atrophy and death.
Skin and subcutaneous tissue disorders: Urticaria, pruritus, erythema, rash.
Very rarely, angioedema has been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
There is limited overdose information involving rifampicin, isoniazid and pyrazinamide in combination.
Signs and Symptoms
Rifampicin
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 to 60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in paediatrics patients ages 1 to 4 years old of 100 mg/kg for one to two doses have been reported.
Isoniazid
Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colours and strange designs), are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycaemia are typical laboratory findings.
Pyrazinamide
There is limited information related to pyrazinamide overdose. Liver toxicity and hyperuricemia may occur with overdosage.
Management
In cases of overdosage with Rifater, gastric lavage should be performed as soon as possible. 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.
Intensive supportive measures should be instituted, including airway patency and individual symptoms treated as they arise.
Isoniazid
If acute isoniazid overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B6) should be considered.
In patients with seizures not controlled with pyridoxine (vitamin B6), anticonvulsant therapy should be administered. Sodium bicarbonate should be given to control metabolic acidosis. Haemodialysis is advised for refractory cases; if this is not available, peritoneal dialysis can be used along with forced diuresis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Rifampicin, isoniazid and pyrazinamide are all active bactericidal antituberculosis drug. Rifampicin and isoniazid are particularly active against the rapidly growing extracellular organisms. Pyrazinamide is active against intracellular organisms, particularly in the acid pH environment of macrophages. Rifampicin and isoniazid also have bactericidal activity intracellularly. Rifampicin has activity against slow and intermittently-growing M Tuberculosis. Thus, the three agents, rifampicin, isoniazid and pyrazinamide have activity against the three different bacterial populations.
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 after the development of resistance to other rifamycins.
5.2. Pharmacokinetic properties
Rifampicin
Rifampicin is readily absorbed from the stomach and the duodenum. Peak serum concentrations of the order of 10 pg/ml occur about 2-4 hours after a dose of 10mg/kg body weight on an empty stomach.
In normal subjects the biological half-life of rifampicin in serum averages about 3 hours after a 600mg dose and increases to 5.1 hours after 900mg 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 the half-life does not differ in patients with renal failure and, consequently, no dosage adjustment is required. The half-life of rifampicin may be decreased when isoniazid is administered concurrently.
After absorption, rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, rifampicin undergoes progressive deacetylation, so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite retains essentially complete antibacterial activity. Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Up to 30% of a dose is excreted in the urine with about half of this being unchanged drug. Absorption of rifampicin is reduced when the drug is ingested with food.
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.
Isoniazid
After oral administration, isoniazid produces peak blood levels within 1 to 2 hours, which decline to 50% or less within 6 hours. Ingestion of isoniazid with food may reduce its absorption. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs and excreta (saliva, sputum and faeces). The drug also passes through the placental barrier and into the milk in concentrations comparable to those in the plasma. From 50 to 70% of a dose of isoniazid is excreted in the urine in 24 hours.
Isoniazid is metabolised primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of Black and Europeans are ‘Slow inactivators’, the majority of Asians are ‘rapid inactivators’.
Pyridoxine deficiency (B6) is sometimes observed in adults with high doses of isoniazid, probably due to its competition with pyridoxal phosphate of the enzyme apotryptophanase.
Pyrazinamide
Pyrazinamide is well absorbed from the gastrointestinal tract and rapidly distributed throughout the body, with peak plasma levels in 2 hours. It is hydrolysed to pyrazinoic acid and then metabolised to 5-hydroxypyrazinoic acid. Glomerular filtration is the primary route of excretion. It is bactericidal in acid pH, and has intracellular antibacterial activity against M. tuberculosis.
Pharmacokinetic studies in normal volunteers have shown that the three ingredients in Rifater have comparable bioavailability whether they are given together as individual dose forms or as Rifater.
5.3. Preclinical Safety Data
Not applicable
6
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Polyvinylpyrrolidone
Sodium Carboxymethylcellulose
Sodium Lauryl Sulphate
Calcium Stearate
Sucrose
Acacia Gum
Talc
Light Magnesium Carbonate Kaolin
Titanum Dioxide Colloidal Silicon Dioxide Aluminium Hydroxide Gel Iron Oxide
6.2. Incompatibilities
None stated
6.3. Shelf Life
4 years from date of manufacture
6.4. Special Precautions for Storage
o
Do not store above 25 C. Store in the original container.
6.5. Nature and Contents of Container
PDVC and PVC/PVDC aluminium foil blisters packed in cardboard cartons. Pack size: 100 tablets
6.6. Instruction for Use/Handling
Not applicable
7 MARKETING AUTHORISATION HOLDER
Aventis Pharma Limited
Trading as Marion Merrell or Aventis Pharma
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
Or trading as
Sanofi-aventis or Sanofi
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 04425/0060
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27 April 1984/10 May 1995
10 DATE OF REVISION OF THE TEXT
10/11/2015