Rifinah 300/150mg Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rifinah 300/150mg Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substances (per tablet):
Rifampicin 300mg Isoniazid 150mg
Excipients (per tablet):
Sucrose 181.03mg E110, Sunset yellow 1.37mg
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Coated tablet
Orange, smooth, shiny capsule shaped sugar coated tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Rifinah is indicated in the treatment of all forms of tuberculosis, including fresh, advanced and chronic cases.
4.2 Posology and method of administration
For oral administration.
Another antituberculosis drug may be given concurrently with Rifinah until the susceptibility of the infecting organism to rifampicin and isoniazid has been confirmed.
Adults: Patients should be given the following single daily dose preferably on an empty stomach at least 30 minutes before a meal or 2 hours after a meal:
Rifinah 150: Patients weighing less than 50kg - 3 tablets. Rifinah 300: Patients weighing 50kg or more - 2 tablets.
Use in the elderly: Caution should be exercised in such patients especially if there is evidence of liver impairment.
4.3 Contraindications
Rifinah is contraindicated in
• patients who are hypersensitive to rifamycins or isoniazid or any of the excipients (see section 6.1);
• the presence of jaundice;
• concurrent treatment with the combination of saquinavir/ritonavir (see section 4.5 Interaction with other medicinal products and other forms of interaction).
4.4 Special warnings and precautions for use
Rifinah is a combination of 2 drugs, each of which has been associated with liver dysfunction.
All tuberculosis patients should have pre-treatment measurements of liver function. 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.
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 occurs.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
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. In these patients, lower doses of rifampicin are recommended and careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 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 rifampicin.
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 (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 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.
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 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 (e.g. 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 Rifinah 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 Rifinah with saquinavir/ritonavir is contraindicated (see section 4.3 Contraindications).
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 withlsoniazid
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 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.
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
Rifampicin has been shown to be teratogenic in rodents when given in large doses. There are no well controlled studies with Rifinah 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 can 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, 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
Rifampicin and isoniazid are excreted in breast milk and infants should not be breast fed by a patient receiving Rifinah 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 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.
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.
Skin and subcutaneous tissue disorders : Rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis and pemphigus.
Rare: toxic epidermal necrolysis, eosinophilia systemic symptoms
Vascular disorders: not known, vasculitis
Hematologic: Eosinophilia, agranulocytosis, thrombocytopenia, anemia, aplastic anaemia and haemolytic anaemia
Gastrointestinal disorder: constipation, dry mouth, nausea, vomiting and
epigastric distress.
not known : Pancreatitis
Hepatobiliary disorders: Uncommon, 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.
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
• 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antimycobacterials, Combinations of drugs for treatment of tuberculosis ATC code: J04AM02
Rifampicin and isoniazid are active bactericidial antituberculosis drugs which are particularly active against the rapidly growing extracellular organisms and also have bactericidal 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.
Isoniazid acts against actively growing tubercle bacilli.
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 a 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.
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.
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). 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.
Pharmacokinetic studies in normal volunteers have been shown that the two ingredients in Rifinah have comparable bioavailability whether they are given together as individual dose forms or as Rifinah.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Sodium lauryl sulphate
Calcium stearate
Sodium carboxymethylcellulose
Magnesium stearate
Microcrystalline cellulose
Magnesium carbonate - light
Carnauba wax
Colophony
White beeswax
Hard paraffin
Sugar coating:
Acacia
Gelatin
Kaolin
Talc
Titanium dioxide (E171) Colloidal silicon dioxide polyvinylpyrollidone K30 Sucrose
Sunset yellow (E110).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Store below 25oC. If it proves necessary to open a blister pack, Rifinah should be dispensed in amber glass or plastic containers. Protect from moisture.
6.5 Nature and contents of container
Blister packs of 56 tablets (4 weeks calendar packs) or of 100 tablets in cardboard cartons.
Blister material is PVC / PVDC and aluminium foil / PVC.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Aventis Pharma Limited One Onslow Street Guildford Surrey
8
9
10
GUI 4YS UK
or trading as:-
Sanofi-aventis or Sanofi
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
10/11/2015