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4.4 Special warnings and precautions for use
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 pre-treatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient’s condition occur.
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.
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.
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)
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 half-life 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
Pyrazinamide antagonizes the effects of probenecid and sulfinpyrazone.
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
Rifampicin
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.
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 child-bearing potential only if the potential benefit justifies the potential risk to the foetus.
Lactation
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
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.
Central Nervous System: Psychoses have been rarely reported.
Disseminated intravascular coagulation has also been rarely reported.
Agranulocytosis has been reported very rarely.
Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.
Anaphylaxis.
Isoniazid
Cutaneous reactions (rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis, pemphigus) and gastrointestinal reactions (pancreatitis, constipation, dry mouth, nausea, vomiting, epigastric distress) have been reported.
Other adverse reactions associated with isoniazid therapy are; hyperglycaemia, gynaecomastia and anti-nuclear antibodies
Pyrazinamide
Skin and subcutaneous tissue disorders: Urticaria, pruritus, erythema, rash.
4.7 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.
