4.4 Special warnings and precautions for use
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Adults treated for tuberculosis with Rifinah 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.
Rifampicin
Rifampicin should be given under the supervision of a respiratory or other suitably qualified physician.
Patients with impaired liver function should only be given rifampicin in cases of necessity, and then with caution and under close medical supervision...........If signs of hepatocellular damage occur, rifampicin should be withdrawn.
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.
4.5 Interaction with other medicinal products and other forms of interaction
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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 Rifinah.
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 Rifinah 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 Rifinah.
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
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.
When rifampicin is taken with para-aminosalicylic acid (PAS), rifampicin levels in the serum may decrease. Therefore, the drugs should be taken at least eight hours apart.
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.
Appropriate adjustments of these drugs should be made.
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.
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
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Pregnancy
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, Rifinah 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
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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
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Rifampicin
Reactions to rifampicin 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 reactions occur but are uncommon. Exfoliative dermatitis, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, Lyells syndrome and vasculitis have been reported rarely.
Gastrointestinal 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 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:
· ‘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 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.
Occasional disturbances of the menstrual cycle have been reported in women receiving long-term antituberculosis therapy with regimens containing rifampicin.
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.
Isoniazid
Hypersensitivity reactions: Fever, anaphylactic reactions.
Nervous system: Vertigo; polyneuritis, presenting as paresthesia, muscle weakness, loss of tendon reflexes, etc, is unlikely to occur with the recommended daily dose of Rifinah. The incidence is higher in "slow acetylators”. Other neurotoxic effects, which are uncommon with conventional doses, are 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.
Cutaneous: Rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis and pemphigus.
Hematologic: Eosinophilia, agranulocytosis, thrombocytopenia, anemia, aplastic anaemia and haemolytic anaemia
Gastrointestinal: Pancreatitis, constipation, dry mouth, nausea, vomiting and epigastric distress.
Hepatic: Severe and sometimes fatal hepatitis may occur with isoniazid therapy.
Reproductive system and breast disorders: gynaecomastia
Investigations: anti-nuclear antibodies
Metabolism and Nutrition Disorders: hyperglycaemia
Miscellaneous: Pellagra, systemic lupus erythematosus-like syndrome.
4.9 Overdose symptoms, emergency procedures, antidotes
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• 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 paediatric 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.
• Management:
In cases of overdosage with Rifinah, 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 .
If acute isoniazide 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, 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.
