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4.4. Special warnings and precautions for use
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).
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. 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.
Because of the possibility of immunological reaction including anaphylaxis (see section 4.8 Undesirable effects) occurring with intermittent therapy (less than 2 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment 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.
Rifadin infusion is for intravenous infusion only and must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection; local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.
4.5 Interaction with other medicinal products and other forms of interaction
Cytochrome P-450 enzyme interaction
Rifampicin is a potent inducer of certain cytochrome P-450 enzymes. Coadministration of rifampicin with other drugs that are also metabolised through these cytochrome P-450 enzymes may accelerate the metabolism and reduce the activity of these other drugs. Therefore, caution should be used when prescribing rifampicin 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 concomitantly administered 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, zolpicolone, 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,
· Analgestics (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 on oral contraceptives should be advised to use alternative, non-hormonal methods of birth control during Rifadin therapy. Also diabetes may become more difficult to control.
Other Interactions
When rifampicin is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifadin with saquinavir/ritonavir is contraindicated (see section 4.3 Contraindications).
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.
Concurrent use of rifampicin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.
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.
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.
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 daily administration of Rifadin for Infusion.
4.6 Pregnancy and lactation
Pregnancy
At very high doses in animals rifampicin has been shown to have teratogenic effects. There are no well controlled studies with rifampicin in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. Therefore, Rifadin for Infusion should be used in pregnant women or in women of child bearing potential only if the potential benefit justifies the potential risk to the foetus. When Rifadin is administered during the last few weeks of pregnancy it may cause post-natal haemorrhages in the mother and infant for which treatment with Vitamin K1 may be indicated.
4.8 Undesirable effects
Reactions occurring with either daily or intermittent dosage regimens include:
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.
Central Nervous System: Psychoses have been rarely reported.
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 reported.
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:
- Anaphylaxis.
4.9 Overdose
Human Experience
• Signs and Symptoms:
Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within a short time after acute ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange colouration of the skin, urine, sweat, saliva, tears and faeces will occur, and its intensity is proportional to the amount ingested. Facial or periorbital oedema has also been reported in paediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.
The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 g rifampicin. Fatal acute overdoses in adults have been reported with doses ranging from 14-60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports.
Nonfatal overdoses in paediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses have been reported.
• Management:
Intensive supportive measures should be instituted and individual symptoms treated as they arise. Since nausea and vomiting are likely to be present, gastric lavage is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting. Active diuresis (with measured intake and output) will help promote excretion of the drug. Haemodialysis may be of value in some patients.
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