Pulmonary and extrapulmonary tuberculosis due to infection with microorganisms susceptible to the combination. If positive cultures persist, new susceptibility tests must be performed in order to rapidly detect the presence of resistant strains. The medicinal product should not be administered prophylactically.

Posology
Adults
Rifinah 150 mg / 100 mg: 3 to 4 tablets per day (equivalent to 450-600 mg of rifampicin and 300-400 mg of isoniazid).
Rifinah 300 mg / 150 mg: 2 tablets per day (equivalent to 600 mg of rifampicin and 300 mg of isoniazid).
Pediatric population
Rifinah is not recommended for pediatric use since the proportion of rifampicin and isoniazid contained in Rifinah makes it difficult to administer a suitable dosage in children.
Method of administration
A single daily dose should be given at least 30 minutes before a meal or 2 hours after a meal.

The concomitant administration of pyridoxine (vitamin B6) is recommended in elderly or malnourished patients or in those with a predisposition to neuropathy (e.g. diabetic patients), and in adolescents.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Rifinah is contraindicated in patients with jaundice. Use of Rifinah is contraindicated during concomitant treatment with the combination of saquinavir+ritonavir (see section 4.5).

Warnings
Rifinah is a combination of two drugs, each of which has been associated with liver dysfunction.
Rifampicin
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, careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST), should be carried out prior to therapy, and then at 2-4 week intervals. If signs of hepatocellular damage occur, rifampicin should be withdrawn.
In some patients, hyperbilirubinemia can occur in the early days of treatment. This results from competition between rifampicin and bilirubin for hepatic excretion. An isolated and moderate increase in bilirubin and/or transaminase levels is not in itself an indication for interrupting treatment; rather the decision should be made after repeated test results have confirmed a tendency towards increasing levels and taking into account the patient's clinical condition.
Because of the possibility of immunological reaction including anaphylaxis (see section 4.8) 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.
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.
Cases of severe skin reactions have been reported with the use of isoniazid, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some with fatal outcome (see section 4.8). Patients should be informed of the signs and symptoms of these reactions and need to be closely monitored. If signs or symptoms of SJS or TEN (i.e. progressive skin rash with blisters or lesions of the mucosa) occur, the patient should be advised to contact his/her treating physician immediately. If it is not possible to establish an alterative etiology for these signs and symptoms, treatment with isoniazid should be discontinued.
Rifampicin/Isoniazid
Severe systemic reactions such as hypersensitivity have been observed during treatment with antitubercular drug therapy, including fatal ones such as drug rash eosinophilia and systemic symptoms (DRESS) (see section 4.8). It is important to keep in mind that hypersensitivity manifestations such as fever, enlarged lymph nodes or biological imbalances (such as eosinophilia or abnormal liver values) may be present even if the skin rash is not evident. If these symptoms occur, the patient should be advised to contact his/her treating physician immediately.

If it is not possible to establish an alternative etiology for these signs and symptoms, treatment with Rifinah should be discontinued.
Severe skin reactions: blisters
Severe skin reactions causing blisters have been reported with the use of rifampicin, such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute generalized exanthematous pustulosis (AGEP). If symptoms or signs of AGEP, SJS or TEN occur, treatment with rifampicin should be immediately discontinued.
Rifinah contains sucrose: therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.
Rifinah 300 mg/150 mg tablets contain sunset yellow, which may cause allergic reactions.
Precautions for use
Adults treated with Rifinah should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count and a platelet count. These baseline measurements are not necessary in children unless they have a known or suspected condition that could give rise to complications.
Patients should be seen at least monthly during therapy and should be questioned specifically about symptoms associated with adverse reactions. All patients with abnormalities of any type 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 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, as a result of induction of delta amino levulinic acid synthetase.
Rifampicin may produce a change in color (yellow, orange, red, brown) of the teeth, urine, sweat, sputum and tears. Patients should be informed of this.
Soft contact lenses may be permanently stained.
Rifampicin is a potent and well-characterized inducer of drug-metabolizing enzymes and carriers and consequently may decrease the exposure and efficacy of any concomitant medication (see section 4.5). Patients therefore need to be informed not to take other drugs without their doctor’s advice.
Rifampicin may cause vitamin-K-dependent coagulopathy and severe bleeding (see section 4.8).
In patients that are more easily prone to bleeding, it is advisable to monitor them for signs of coagulopathy. When appropriate (vitamin K deficiency, hypoprothrombinemia), the possibility of prescribing vitamin K supplements should be considered.
Isoniazid
Care should be exercised in the treatment of elderly or malnourished patients who may also require vitamin B6 supplementation with the isoniazid therapy.

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. tuna, tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving Rifinah.

Pharmacodynamic interactions
Rifinah
When Rifinah 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).
Cytochrome P-450 enzyme interaction
Rifampicin is known to induce and isoniazid is known to inhibit certain cytochrome P-450 enzymes. 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 metabolized by cytochrome P-450. To maintain optimum therapeutic blood levels, dose adjustment of drugs metabolized by these enzymes may be required when starting or stopping Rifinah.
Rifampicin
When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. Therefore, the concomitant use of rifampicin and halothane should be avoided. Patients receiving both rifampicin and isoniazid should be monitored closely for hepatotoxicity.
The concomitant use of rifampicin with other antibiotics that cause vitamin-K-dependent coagulopathy such as cefazolin (or other cephalosporins with side chains of N-methylthiotetrazole) may seriously disrupt normal coagulation and even result in death (especially at high doses). If this combination cannot be avoided, the patient needs to be clinically monitored, making sure to also check for any hemostasis.
Rifampicin effects on other drugs
Induction of drug-metabolizing enzymes and carriers
Rifampicin is a potent and well-characterized inducer of drug-metabolizing enzymes and carriers. Enzymes and carriers that are found to be influenced by Rifadin include cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19 and 3A4, and UDP-glucuronosyltransferase (UGT), sulfur transferases, carboxylesterases and carriers, including P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2). Most drugs are substrates of these enzymatic routes or carriers and the routes can be simultaneously induced by rifampicin. Therefore, rifampicin may speed up metabolism and reduce the activity of some concomitant medications, while also causing clinically significant drug-drug interactions with several drugs and drug classes. At the start of treatment with rifampicin or at the time of its discontinuation, it may prove necessary to adjust the dose of the concomitant drugs in order to maintain therapeutically ideal blood concentration levels.
Below are some examples of the induction effect of rifampicin during exposure to specific drug-metabolizing enzymes or drug carrier substrates. For the drugs and drug classes indicated below, the simultaneous administration of rifampicin led to decreased exposure to the drug itself and to its metabolite:
ANTIMICROBIAL DRUGS
Antiviral drugs
Antiretroviral drugs (e.g. zidovudine, saquinavir, indinavir, efavirenz) (see also section 4.3 Contraindications):
600 mg of rifampicin per day reduced the exposure to zidovudine (AUC) by 47% via glucuronidation induction and via the metabolic amination pathway of zidovudine;
600 mg of rifampicin per day reduced the exposure to saquinavir (AUC) by 70% in healthy volunteers and by 47% in patients with HIV, most likely via CYP3A4 induction and possibly via the P-gp routes;

600 mg of rifampicin per day reduced the exposure (AUC) to efavirenz by 60%, mainly via induction of the 8-hydroxylation pathway of CYP2B6-mediated efavirenz.
Antiviral drugs for hepatitis C (e.g. daclatasvir, simeprevir, sofosbuvir, telaprevir):
Antiviral drugs for hepatitis C are eliminated by the various drug-metabolizing enzymes and carriers, which are susceptible to induction with multiple-dose rifampicin.
600 mg of rifampicin per day reduce the exposure (AUC) to daclatasvir by 79%, to simprevir by 48%, to sofosbuvir by 77% and to telaprevir by 92% compared to control subjects.
The concomitant use of antiviral anti-hepatitis C drugs and rifampicin should be avoided.
Antifungal drugs
Antifungal drugs (e.g. fluconazole, itraconazole, ketoconazole):
600 mg of rifampicin per day reduce the exposure (AUC) to fluconazole by approximately 23%, to itraconazole by 88% and to ketoconazole by about 80%.
Antibacterials
Chloramphenicol:
In two children treated simultaneously with chloramphenicol and rifampicin iv, the peak serum concentrations of chloramphenicol were reduced by 85.5% in one patient and by 63.8% in the other.
Clarithromycin:
600 mg of rifampicin per day significantly reduced the blood concentration levels of clarithromycin and increased the concentration levels of the clarithromycin metabolite.
Doxycycline:
In a group of hospitalized patients, rifampicin (10 mg/kg per day) reduced the exposure (AUC) to doxycycline by roughly 50%.
Fluoroquinolones:
900 mg per day of rifampicin moderately reduced the AUC of pefloxacin by about 35%. 450 mg to 600 mg of rifampicin per day were found to reduce the exposure (AUC) to moxifloxacin by approximately 30%.
Telithromycin:
Telithromycin is primarily metabolized by CYP3A4. 600 mg of rifampicin per day reduced the exposure (AUC) to telithromycin by 86%.
Antimycobacterial drugs
Dapsone:
In a clinical study with a cocktail of medicinal products, 600 mg of rifampicin per day increased dapsone metabolism via induction of CYP2C9, CYP2E1 and CYP3A4.
ANTIEPILEPTIC DRUGS
Anticonvulsants (e.g. phenytoin):
Phenytoin is primarily metabolized by CYP2C9/2C19. 450 mg of rifampicin per day doubled phenytoin clearance and reduced its half-life by about 50%.

Barbiturates:
It has been proven that rifampicin increases the metabolic clearance of hexobarbital by 2 to 3 times in healthy volunteers and in patients, while also significantly reducing the half-life of hexobarbital.
PSYCHOTROPIC DRUGS
Antipsychotics (e.g. haloperidol):
Concomitant administration of rifampicin to schizophrenic patients receiving haloperidol led to a decrease in the minimum haloperidol concentrations of up to 70%.
Benzodiazepines (e.g. diazepam):
600 and 1200 mg of rifampicin per day increased diazepam clearance by 60 and 98%, respectively.
Benzodiazepine equivalents (e.g. zopiclone, zolpidem):
600 mg of rifampicin per day reduced the exposure (AUC) to zopiclone by 82% and to zolpidem by 27%.
Tricyclic antidepressants (e.g. nortriptyline):
600 mg per day of rifampicin as part of a tuberculosis treatment regimen that also included 300 mg of isoniazid per day, 500 mg of pyrazinamide three times per day and 25 mg of pyridoxine were linked to higher-than-expected doses of nortriptyline to obtain a therapeutic level of the drug. After discontinuing rifampicin, the patient experienced drowsiness and the serum levels of nortriptyline abruptly increased (3 times) reaching toxic levels.
CARDIOVASCULAR SYSTEM
Substances acting on the renin-angiotensin system, ACE-inhibitors
Enalapril:
If required due to the patient’s clinical condition, the dose needs to be adjusted.
Antiarrhythmic drugs (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide):
600 mg of rifampicin per day reduced the exposure (AUC) to mexiletine by 41%, to quinidine by approximately 80%, to propafenone by 87% and to tocainide by 25%.
Beta blockers:
600 mg of rifampicin per day reduced the exposure (AUC) to metoprolol by 33% and increased propranolol clearance by 169%.
Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil):
Calcium channel blockers are largely CYP3A4 substrates.
The administration of 1200 mg of rifampicin as single oral dose 8 hours before the administration of a single dose of 10 mg of nifedipine reduced the exposure to nifedipine by 64%.
600 mg of rifampicin per day reduced the exposure (AUC) to verapamil by 93%.
Cardioactive glycosides:
Digoxin is a clinical index substrate for P-gp activity.
600 mg of rifampicin per day reduced oral digoxin bioavailability by 30% and produced an increase of 3.5 times the content of intestinal P-gp linked to the AUC following oral digoxin.
Numerous reports have been published with regard to the interaction of digoxin and rifampicin. A drop in the serum levels of digoxin was observed during antitubercular therapy with rifampicin-isoniazid-ethambutol or with rifampicin alone: the digoxin serum levels decreased by 53% and 54% respectively.

Angiotensin II receptor blockers
Losartan:
Losartan is metabolized by CYP2C9 and by CYP3A4 in an active metabolite E3174, which has a greater antihypertensive activity than the parent compound.
600 mg of rifampicin per day reduced the exposure (AUC) to losartan by 35% and to E3174 by 40%. Losartan oral clearance increased by 44%. The half-life values of both compounds decreased by 50%.
Statins metabolized by CYP3A4 (e.g. simvastatin):
Simvastatin is a clinical index substrate of CYP3A4.
600 mg per day of rifampicin reduced the exposure (AUC) to simvastatin by 87% compared to placebo. Because the half-life elimination of simvastatin is not affected by rifampicin, metabolism induction at the first CYP3A4-mediated passage of simvastatin in the intestine and liver likely explain this interaction.
Clofibrate: 600 mg of rifampicin per day significantly decreased the blood concentration levels at the stationary state of the main circulating metabolite of clofibrate, chlorophenoxyisobutyric acid (CPIB), from 50 μg/ml to 33 μg/ml. Although the half-life of CPIB in the blood in individual subjects dropped during treatment with rifampicin, the change was not significant. ANTITHROMBOTIC DRUGS Oral anticoagulants (e.g. warfarin): S-warfarin is a clinical index substrate for CYP2C9. 600 mg of rifampicin per day reduced the exposure (AUC) to S-warfarin by 74%. ANALGESICS Narcotic analgesics: Various studies and clinical cases were reviewed between rifampicin and opioid analgesics. 600 mg of rifampicin per day decreased the average AUC of IV injectable and oral oxycodone by 53% and 86% respectively, while the average bioavailability of oral oxycodone decreased by 70%. 600 mg of rifampicin per day reduced the Cmax of morphine by 41% and the AUC by 28%. The pain-relieving effect of morphine needs to be monitored and the morphine doses adjusted during and after treatment with rifampicin. Metadone: Metadone is primarily metabolized by CYP2B6 and CYP3A4. 600 mg of rifampicin decreased the oral bioavailability of metadone from 70% to 50%. HORMONES AND OTHER ENDOCRINE THERAPIES Systemic hormonal contraceptices, including estrogens and progestins: Treatment with rifampicin decreases the systemic exposure of oral contraceptives. Patients who use systemic hormonal contraceptives should be advised to switch to non-hormonal contraceptive methods during therapy with rifampicin. Antiestrogens (e.g. tamoxifen, toremifene): Tamoxifen and toremifene are largely CYP3A4 substrates. 600 mg of rifampicin per day reduced systemic exposure (AUC) to tamoxifen by 86% and to toremifene by 87%.

Corticosteroids: Numerous cases reported in the literature describe a decrease in the glucocorticoid effects when rifampicin is simultaneously prescribed. The literature contains reports of acute adrenal crisis or adrenal insufficiency induced by the combination of rifampicin-isoniazid-ethambutol or rifampicin-isoniazid in patients with Addison’s disease. In patients who receive concomitant treatment with rifampicin, the AUC of prednisolone dropped from 48% to 66% and the clearance increased from 45% to 91%. Levothyroxine: 600 mg of rifampicin per day were given to a patient previously treated with levothyroxine. About two weeks after starting therapy with rifampicin, the concentration of thyroid-stimulating hormone (TSH) increased by 202% compared to the concentration level prior to treatment. TSH concentration returned within normal ranges 9 days after having discontinued the rifampicin. GASTROINTESTINAL TRACT and METABOLISM 5-HT3 selective antagonists (e.g. ondansetron): Ondansetron is metabolized by multiple CYP enzymes. 600 mg of rifampicin per day reduced exposure (AUC) to orally administered ondansetron by 65% compared to placebo and the elimination half-life (t ½) by 38%. The oral bioavailability of ondansetron dropped from 60 to 40%. Thiazolidinediones (e.g. rosiglitazone): Rosiglitazone is primarily metabolized by CYP2C8 and to a lesser degree by CYP2C9. 600 mg of rifampicin per day increased the oral clearance of rosiglitazone by 3 times while reducing exposure (AUC) by 65% and the elimination half-life from 3.9 to 1.5 hours. Oral hypoglycemic agents (e.g. sulfonylureas): Sulfonylureas are mainly CYP2C9 substrates. 600 mg of rifampicin per day reduced the exposure (AUC) of glyburide by 39% and of glipizide by 22% and reduced the half-life of both drugs. It is likely that glyburide’s effect of lowering the levels of glucose in the blood is reduced during concomitant treatment with rifampicin. ANTINEOPLASTIC DRUGS Irinotecan: Irinotecan is widely metabolized by various enzymatic systems, including carboxylesterase, UGT and CYP3A4. 450 mg per day of rifampicin were given to a patient as part of an antibiotic regimen including isoniazid (300 mg per day) and streptomycin (0.5 mg per day via IM injection). Although no change in the exposure (AUC) to irinotecan was observed, the exposure (AUC) to the active metabolite of irinotecan dropped by 20% and to its metabolite glucuronide by 58.8%, likely due to CYP3A4 induction. IMMUNOSUPPRESSANTS Immunosuppressants (e.g. cyclosporine, tacrolimus): Cyclosporine and tacrolimus are substrates of CYP3A4 and P-gp. In six healthy volunteers, the bioavailability of cyclosporine dropped from 33% to 9% with the concomitant administration of 600 mg of rifampicin per day. In four patients with kidney transplant, the concomitant administration of 600 mg of rifampicin per day reduced the exposure (AUC) to cyclosporine by approximately 60%. In six healthy volunteers, the oral bioavailability of tacrolimus was decreased by 51% following the concomitant administration of 600 mg of rifampicin per day via CYP3A4 and P-gp induction.

ANTI-PARASATIC DRUGS

Praziquantel:

Praziquantel is largely metabolized by CYP enzymes. 600 mg of rifampicin per day reduced the concentrations of praziquantel in the blood below measurable levels in 7 out of 10 subjects treated with a single dose of praziquantel. In 3 subjects with measurable concentraction levels, exposure (AUC) to praziquantel was reduced by 85%. In the same study, rifampicin reduced the concentrations of multiple-dose praziquantel below measurable levels in 5 out of 10 subjects. In 5 subjects with measurable concentration levels, exposure to praziquantel (AUC) was reduced by 80%. Quinine: Quinine is predominantly metabolized by CYP3A4. 600 mg of rifampicin per day increased quinine clearance by 6.9 times and reduced its exposure (AUC) and half-life.

RESPIRATORY SYSTEM Other drugs for obstructive syndromes of the respiratory tract for systemic use, xanthine derivatives: Theophylline Theophylline is clinical index inhibitor of CYP1A2. 600 mg of rifampicin per day increased theophylline clearance by 40%, reduced exposure (AUC) to theophylline by 27% and reduced the elimination half-life by 30%.

Effect of other drugs on rifampicin

The simultaneous intake of antacids may reduce rifampicin absorption. The daily dose of rifampicin should be taken at least 1 hour before taking the antacids. Interactions of other drugs with rifampicin With the concomitant administration of atovaquone and rifampicin, reduced concentrations of atovaquone and increased concentrations of rifampicin have been observed.
Isoniazid
It has been reported that isoniazid inhibits the metabolism of carbamazepine and phenytoin.
Other Interactions: para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competing for acetylating enzymes.
Interference with laboratory and diagnostic tests
Therapeutic levels of rifampicin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Alternative assay methods must therefore be used.
In addition, transient elevation of serum bilirubin has been reported (see section 4.4). Rifinah 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 Rifinah.
Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampicin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method. Confirmatory tests, such as gas chromatography and mass spectrometry, are able to distinguish rifampicin from opiates.

Pregnancy
There are no well controlled studies with Rifinah in pregnant women.

Rifampicin
Rifampicin has been shown to be teratogenic in rodents when given in large doses.
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 fetus is not known.
When administered during the last few weeks of pregnancy, rifampicin can cause post-natal hemorrhages in the mother and infant, for which treatment with vitamin K 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).
Rifinah
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 fetus.
No data are available concerning the long-term effects on human fertility.
Lactation
Rifampicin and isoniazid are excreted in breast milk. Therefore Rifinah should only be used by breast-feeding women if the potential benefit to the patient outweighs the potential risk to the infant.

Rifinah may cause undesired effects that may impair the ability to perform certain activities (see section 4.8). Patients should be informed of the possibility that these undesired effects may occur and that if they do occur, they should seriously consider not driving or using machines.

The following adverse reactions may occur, which are classified by system-organ class and by frequency applying the following convention: 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 (the frequency cannot be estimated from the available data)
Rifampicin
Infections and infestations
Not known: pseudomembranous colitis, influenza.
Blood and lymphatic system disorders
Common: thrombocytopenia with or without purpura may occur, usually associated with intermittent therapy, but is reversible if the drug is discontinued as soon as purpura occurs.
Uncommon: leukopenia.
Not known: disseminated intravascular coagulation, eosinophilia, agranulocytosis, hemolytic anemia, vitamin K-dependent coagulation disorders.
Immune system disorders
Not known: anaphylactic reaction.
Endocrine disorders
Not known: adrenal insufficiency in patients with impaired adrenal function.
Metabolism and nutrition disorders
Not known: decreased appetite.

Psychiatric disorders
Not known: psychotic episodes.
Nervous system disorders
Common: migraine, dizziness.
Not known: cerebral hemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura.
Eye disorders
Not known: change in color of tears.
Vascular disorders
Not known: shock, hot flashes, vasculitis, bleeding.
Respiratory, thoracic and mediastinal disorders
Not known: shortness of breath, wheezing, change in color of sputum.
Gastrointestinal disorders
Common: nausea, vomiting.
Uncommon: diarrhea.
Not known: gastrointestinal disorders, abdominal discomfort, change in color of teeth (which may be permanent).
Hepatobiliary disorders
Not known: hepatitis, hyperbilirubinemia (see section 4.4).
Skin and subcutaneous tissue disorders
Not known: erythema multiforme, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4), skin reactions, itching, itchy rash, hives, allergic dermatitis, pemphigus, change in color of sweat.
Musculoskeletal and connective tissue disorders
Not known: muscle weakness, myopathy, bone pain.
Renal and urinary disorders
Not known: acute renal failure generally due to renal tubular necrosis or tubulo-interstitial nephritis, chromaturia.
Pregnancy, puerperium and perinatal conditions
Not known: post-partum hemorrhage, maternal-fetal hemorrhage.
Reproductive system and breast disorders
Not known: menstrual disorders.
Congenital, familial and genetic disorders
Not known: porphyria.
General disorders and administration site conditions
Very common: fever, shivers.
Not known: edema.

Investigations
Common: increased bilirubin in blood, increased aspartate aminotransferase, increased alanine aminotransferase.
Not known: decreased blood pressure, increased creatinine in blood, increased liver enzymes.
Isoniazid
Hypersensitivity reactions: fever, anaphylactic reactions.
Endocrine disorders: gynecomastia.
Nervous system disorders: polyneuritis, presenting as paresthesia, muscle weakness, loss of tendon reflexes, etc. The incidence is higher in "slow acetylators”. Other neurotoxic effects, which are uncommon with conventional doses, include convulsions (see section 4.9), toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis.
Skin and subcutaneous tissue disorders: rash, acne, exfoliative dermatitis, pemphigus, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) (see section 4.4) and drug reaction with eosinophilia and systemic symptoms (DRESS) (“rare” frequency) (see section 4.4).
Blood and lymphatic system disorders: eosinophilia, agranulocytosis, thrombocytopenia, anemia.
Gastrointestinal disorders: pancreatitis (“not known” frequency), nausea, vomiting, epigastric distress.
Hepatobiliary disorders: hepatitis (“uncommon” frequency), including severe and sometimes fatal.
Vascular disorders: vasculitis (“not known” frequency).
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 the national reporting system at the following link: www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
To reports any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
KSA_Pharmacovigilance@sanofi.com

Experience in humans: limited data are available concerning the isoniazid and rifampicin combination.
Symptoms
Rifampicin

Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy may occur within a short time after acute ingestion; unconsciousness may occur when there is severe hepatic disease. The following may occur: transient increases in liver enzymes and/or bilirubin and a brownish-red or orange coloration of the skin, urine, sweat, saliva, tears and feces, with an intensity proportional to the amount ingested. Facial or periorbital edema has also been reported in pediatric 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 pediatric patients aged 1 to 4 years old treated with 100 mg/kg (1 or 2 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 colors 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 hyperglycemia are typical laboratory findings.
Treatment
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 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, anticonvulsant therapy should be administered. Sodium bicarbonate should be given to control metabolic acidosis. Hemodialysis is advised for refractory cases; if this is not available, peritoneal dialysis can be used along with forced diuresis.

Pharmacotherapeutic group: Antimycobacterials, combinations of drugs for treatment of tuberculosis; ATC code: J04AM02
Rifampicin and isoniazid are active bactericidal antituberculosis drugs which are particularly active against the rapidly growing extracellular organisms and also have bactericidal activity intracellularly.
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. Rifampicin has activity against slow- and intermittently-growing M. tuberculosis.
Isoniazid acts against actively growing tubercle bacilli.

Pharmacokinetic studies in normal volunteers have shown that the two ingredients in Rifinah have comparable bioavailability whether they are given together as individual dose forms or as Rifinah.

Rifampicin
Rifampicin administered orally is readily absorbed from the gastrointestinal tract. Peak blood levels in adults and children vary widely from individual to individual. Peak serum concentrations of the order of 10 μg/ml occur about 2-4 hours after an oral dose of 10 mg/kg body weight on an empty stomach. Absorption of rifampicin is reduced when the drug is ingested with food.
In normal subjects the biological half-life of rifampicin in serum averages about 3 hours after a 600 mg dose and increases to 5.1 hours after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2-3 hours.
At a dose of 600 mg/day, the half-life does not differ in patients with renal failure and consequently, no dose adjustment is required.
After absorption (oral or IV), 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 antibacterial activity.
Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Approximately 30% of a dose is excreted in the urine, with about half of this being unchanged drug. 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 feces). The drug passes through the placental barrier and into 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 metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators", while the majority of Asians are "rapid inactivators”.

Carcinogenesis
Rifampicin
No data are available in humans concerning the long-term carcinogenic potential. A few cases of exacerbation of lung cancer in humans have been reported but no causal relationship has been determined with the drug. An increase in the incidence of hepatomas was observed in female mice (of a strain particularly susceptible to the spontaneous development of hepatomas) following the administration of rifampicin in quantities equivalent to 2-10 times the average dose in humans for 60 weeks, followed by an observation period of 46 weeks. No carcinogenesis was demonstrated in male mice of the same strain or in rats in similar experimental conditions.
Rifampicin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro and humans.
An antitumor activity of rifampicin has been reported in vitro.
Isoniazid
Isoniazid has been reported to cause lung tumors in various strains of mice.
Mutagenesis
No data are available in humans concerning the long-term mutagenic potential of Rifinah. No mutagenic effects of rifampicin have been demonstrated in bacteria, Drosophila melanogaster or mice. An increase in chromatid breaks was noted when human whole blood cell cultures were treated with rifampicin. In vitro,

an increase in the frequency of chromosomal aberrations has been observed in lymphocytes obtained from patients treated with combinations of rifampicin, isoniazid and pirazinamide and combinations of streptomycin, rifampicin, isoniazid and pirazinamide

Rifinah 300 mg / 150 mg coated tablets: Sodium lauryl sulfate, calcium stearate, sodium carboxymethyl cellulose, microcrystalline cellulose, gelatin, sucrose, talc, magnesium carbonate, titanium dioxide (E171), kaolin, aluminum lake and sunset yellow (E110), magnesium stearate, acacia, colloidal silicon dioxide, polyvinylpyrolidone K30.

There are no known incompatibilities with other drugs.

3 years.

Store below 30°C.

Rifinah 300 mg/150 mg coated tablets Blister pack of 8 coated tablets. Blister pack of 24 coated tablets.

Rifinah 300 mg/150 mg coated tablets Blister pack of 8 coated tablets.

No special requirements for disposal.