Infections caused by rifampicin-susceptible microorganisms, particularly Mycobacterium tuberculosis and other mycobacteria. In mycobacterial infections, this medicinal product should be used in conjunction with other antibiotics or specific chemotherapeutic agents. For infections other than tuberculosis, concomitant administration of another active antibiotic is recommended to prevent development of resistance. The susceptibility of pathogens, or their possible primary or acquired resistance, should be determined by means of an antibiotic susceptibility test, as is generally required for the appropriate use of antibiotics.
If the infection does not respond to treatment within a reasonable period of time, treatment should be changed, and if relapse occurs, administration of rifampicin is advised only after carrying out preliminary bacteriological tests.

Oral Rifadin
Posology
Adults: in the treatment of tuberculosis, 600 mg daily as a single dose in patients weighing more than 50 kg (450 mg in patients weighing less than 50 kg), in conjunction with other antituberculosis drugs. For other infections, the daily dose may reach 900-1200 mg, and is usually divided into two doses.
Pediatric population: the recommended daily dose is 10-20 mg/kg body weight divided into two equal doses. A daily dose of 600 mg should not be exceeded.

The bottle must be shaken well but gently in order to avoid foaming.
The measuring cup should be rinsed thoroughly with water after measuring out the syrup.
Method of administration
For faster and more complete absorption, Rifadin should be taken on an empty stomach and not at meal times (at least 30 minutes before a meal or 2 hours after a meal).
In newly confirmed cases, treatment is most effective when continuous and administered for a short time, i.e. 9 months, at the doses given above, in combination with isoniazid and, for the first 3 months, a third antituberculosis agent.
Rifadin solution for infusion
Posology
Dose in non-specific infections: the recommended daily dose for adults is 600 mg (as determined by the doctor: one 600 mg vial daily).
Dose in pulmonary tuberculosis: the recommended daily dose for adults is 600 mg, generally as a single dose. The treatment of pulmonary tuberculosis with Rifadin for infusion should provide for the concomitant use of other antituberculosis drugs.
Method of administration
Rifadin is available in a vial (containing 600 mg of antibiotic) with a solvent ampoule. Rifadin for intravenous infusion is particularly recommended when oral administration of the antibiotic is not possible or not recommended due to the clinical status of the patient (surgical procedures, impaired gastrointestinal absorption etc.) or due to gastric intolerance.
The solution is prepared by adding the solvent from the ampoule included in the pack to the vial of rifampicin and shaking vigorously and continuously for about 30 seconds.
As soon as the foam has completely disappeared, the solution should be diluted in 500 mL of 5% glucose solution or normal saline. Prepared solutions should be used within a few hours (see section 6.3). The drip rate should be adjusted so that the infusion lasts for about 3 hours.

Rifadin must not be used for the treatment of non-tubercular infections if an associated tubercular form is suspected, until the diagnosis has been confirmed, so as not to mask the tubercular process or cause mycobacterial resistance.
Special caution must be exercised in malnourished elderly subjects and in young children, particularly when isoniazid is coadministered.
Liver
Patients with impaired liver function should only be given Rifadin in cases of necessity and then with caution and under strict 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 every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, Rifadin should be discontinued.
In some cases, hyperbilirubinemia resulting from competition between Rifadin and bilirubin for excretory pathways of hepatocytes can occur in the early days of treatment. 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.

Immunological reactions/anaphylaxis
Because of the possibility of immunological reactions including anaphylaxis 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.
Severe systemic hypersensitivity reactions
Severe, systemic hypersensitivity reactions, including fatal cases, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been observed during treatment with antituberculosis therapy (see section 4.8). It is important to note that early manifestations of hypersensitivity, such as fever, lymphadenopathy or biological abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be advised to consult immediately their physician.
Rifadin should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Severe bullous reactions
Cases of severe bullous skin reactions such as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) have been reported with rifampicin. If symptoms or signs of AGEP, SJS or TEN are present, rifampicin treatment must immediately be discontinued.
Rifadin syrup
Rifadin syrup contains:
- sucrose and, as such, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product. This medicinal product contains 12 g of sucrose per dose (600 mg). This should be taken into account in patients with diabetes mellitus. It may also be harmful to the teeth.
- sodium metabisulfite, which may cause allergic-type reactions in some sensitive patients,

including anaphylactic symptoms and asthma attacks (bronchospasm) which may be life-threatening for the patient.
- methyl parahydroxybenzoate and propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).
Rifadin coated tablets
Rifadin tablets contain:
- lactose and, as such, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
- sucrose and, as such, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.
Rifadin powder and solvent for solution for infusion contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.
Precautions
Adults treated with Rifadin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count. Baseline tests are unnecessary in children unless a complicating condition is known or clinically suspected.
Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary.
Rifadin 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 Rifadin administration as a result of induction of delta amino levulinic acid synthetase.
Rifadin may produce a change in color of the urine, sweat, sputum, and tears and the patient should be forewarned of this.
Soft contact lenses have been permanently stained.

Rifadin is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease concomitant drug exposure and efficacy (see section 4.5). Therefore, patients should be advised not to take any other medication without medical advice.
Rifampicin may cause vitamin K dependent coagulopathy and severe bleeding (see section 4.8).
Monitoring of occurrence of coagulopathy is recommended for patients at particular bleeding risk. Supplemental vitamin K administration should be considered when appropriate (vitamin K deficiency, hypoprothrombinemia).
Rifadin solution in vials is for intravenous infusion only and must not be administered by the 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.

Pharmacodynamic interactions
When Rifadin 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).
When Rifadin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of Rifadin and halothane should be avoided. Patients receiving both Rifadin and isoniazid should be monitored closely for hepatotoxicity.
The concomitant use of rifampicin with other antibiotics causing vitamin K dependent coagulopathy such as cefazolin (or other cephalosporins with N-methyl-thiotetrazole side chains) should be avoided as it may lead to severe coagulation disorders, which may result in fatal outcome (especially with high doses). If this combination cannot be avoided, clinical monitoring, possibly including hemostatic monitoring, is required.
Effect of Rifadin on other medicinal products
Induction of drug metabolizing enzymes and transporters
Rifadin is a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifadin include cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 3A4 and UDP-glucoronlytransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most drugs are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced by Rifadin simultaneously. Therefore, Rifadin may accelerate the metabolism and reduce the activity of certain co-administered drugs, and has the potential to perpetuate clinically important drug-drug interactions against many drugs and across many drug classes. To maintain optimum therapeutic blood levels, dosage of drugs may require adjustment when starting or stopping concomitantly administered Rifadin.
The following table provides examples of the induction effect of rifampicin on exposure of selected drug metabolizing enzymes and transporter substrate drugs. Concomitant administration of rifampicine with the following drugs or class of drugs has demonstrated a decrease in drug or metabolite exposure.
ANTIMICROBIALS
Antiviral drugs
Antiretroviral drugs (e.g. zidovudine, saquinavir, indinavir, efavirenz) (see also section 4.3 “Contraindications):
Rifampicin 600 mg daily reduced zidovudine exposure (AUC) by 47% via induction of zidovudine glucuronidation and amination metabolism pathways;
Rifampicin 600 mg daily reduced saquinavir exposure (AUC) by 70% in healthy volunteers and by 47% in HIV-infected patients most likely via induction of CYP3A4 and possibly P-gp pathways;
Rifampicin 600 mg daily reduced efavirenz exposure (AUC) by 60% primarily via induction of efavirenz CYP2B6-mediated 8-hydroxylation pathway.

Hepatitis-C antiviral drugs (e.g. daclatasvir, simeprevir, sofosbuvir, telaprevir):
The hepatitis C antivirals are cleared by various drug metabolizing enzymes and transporters which are susceptible to induction by multiple dose rifampicin.
Rifampicin 600 mg daily reduced the exposure (AUC) of daclatasvir by 79%, simeprevir by 48%, sofosbuvir by 77% and telaprevir by 92% compared to control subjects.
Concurrent use of treatment of hepatitis-C antiviral drugs and rifampicin should be avoided.
Antifungals
Antifungals (e.g. fluconazole, itraconazole, ketoconazole):
Rifampicin 600 mg daily reduced fluconazole exposure (AUC) by approximately 23%, itraconazole by 88% and ketoconazole by about 80%.
Antibacterials
Chloramphenicol:
In two children treated concomitantly with intravenous chloramphenicol and rifampin, peak chloramphenicol serum concentrations were reduced by 85.5% in one patient and by 63.8% in the other.
Clarithromycin:
Rifampicin 600 mg daily markedly reduced plasma concentrations of clarithromycin and increased clarithromycin metabolite concentrations.
Doxycycline:
In a group of hospitalized patients rifampicin (10 mg/kg daily) reduced the exposure (AUC) of doxycycline by about 50%.
Fluoroquinolones:
Rifampicin 900 mg daily modestly reduced the AUC of perfloxacin by about 35%. Rifampicin 450 mg to 600 mg daily has been shown to reduce the exposure (AUC) of moxifloxacin by about 30%.
Telithromycin:
Telithromycin is metabolized primarily by CYP3A4. Rifampicin 600 mg daily reduced telithromycin exposure (AUC) by 86%.
Antimicrobacterials
Dapsone:
In a clinical probe cocktail study, rifampicin 600 mg daily, increased the metabolism of dapsone via induction of CYP2C9, CYP2E1 and CYP3A4.
ANTIEPILEPTICS
Anticonvulsants (e.g. phenytoin):
Phenytoin is metabolized mainly by CYP2C9/2C19. Rifampicin 450 mg daily doubled the clearance of phenytoin and reduced the half-life by about 50%.
Barbiturates:
Rifampicin has been shown to increase hexobarbital metabolic clearance by 2- to 3-fold in healthy volunteers and patients, and to significantly decrease hexobarbital half-life.
ANTIPSYCHOTICS
Antipsychotics (e.g. haloperidol):
Coadministration of rifampicin to schizophrenic patients receiving haloperidol decreased haloperidol trough concentrations up to 70%.
Benzodiazepines (e.g. diazepam):
Rifampicin 600 and 1200 mg daily increased the clearance of diazepam by 60% and 98%, respectively.
Benzodiazepine-related drugs (e.g. zopiclone, zolpidem):
Rifampicin 600 mg daily reduced the exposure (AUC) of zopiclone by 82% and of zolpidem by 27%.

Tricyclic antidepressants (e.g. nortriptyline):
Rifampicin 600 mg daily as part of a tuberculosis treatment regimen that included isoniazid 300 mg daily, pyrazinamide 500 mg 3x per day and pyridoxine 25 mg was associated with higher than expected doses of nortriptyline were required to obtain a therapeutic drug level. Following the discontinuation of rifampicin, the patient became drowsy and the serum nortriptyline levels rose precipitously (3-fold) into the toxic range.
CARDIOVASCULAR SYSTEM
Substances that act on the renin-angiotensin system, ACE inhibitors
Enalapril:
Dosage adjustments should be made if indicated by the patient's clinical condition.
Antiarrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide):
Rifampicin 600 mg daily reduced the exposure (AUC) of mexiltine by 41%, quinidine by about 80%, propafenone by 87%, and tocainide by 25%.
Beta-blockers:
Rifampicin 600 mg daily reduced the exposure (AUC) of metoprolol by 33% and increased the clearance of propranolol by 169%
Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil):
Calcium channel blockers are primarily substrates of CYP3A4.
Rifampicin 1200 mg administered as a single oral dose 8 h before administering a single oral dose of nifedipine 10 mg reduced nifedipine exposure (AUC) by 64%.
Rifampicin 600 mg daily reduced the exposure (AUC) of verapamil by 93%.
Cardiac glycosides:
Digoxin is a clinical index substrate for P-gp activity.
Rifampicin 600 mg daily reduced the bioavailability of oral digoxin by 30% and increased intestinal P-gp content 3.5-fold, which correlated with the AUC after oral digoxin.
Several reports have been published regarding the interaction of digitoxin and rifampicin. Decreased serum digitoxin levels were observed during antituberculosis therapy with rifampicin-isoniazid-ethambutol or with rifampicin alone; serum digitoxin levels decreased by 53% and 54% respectively.
Angiotensin-II antagonists
Losartan:
Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound.
Rifampin 600 mg daily reduced the exposure (AUC) of losartan by 35% and E3174 by 40%. Losartan oral clearance was increased by 44%. The half-life values of both compounds were decreased by 50%.
Statins metabolized by CYP3A4:
Simvastatin is a clinical index substrate of CYP3A4.
Rifampicin 600 mg daily reduced simvastatin exposure (AUC) by 87% compared to placebo. Because the elimination half-life of simvastatin was not affected by rifampicin, induction of the CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and the liver probably explains this interaction.
Clofibrate:
Rifampicin 600 mg daily significantly reduced steady-state plasma concentrations of clofibrate’s main circulating metabolite, chlorophenoxyisobutyric acid (CPIB), from 50 micrograms/mL to 33 micrograms/mL. Although CPIB plasma half-life of individual subjects was decreased during rifampicin treatment, the change was not significant.
ANTITHROMBOTICS
Oral anticoagulants (e.g. warfarin):
S-Warfarin is a clinical index substrate for CYP2C9. Rifampicin 600 mg daily reduced the exposure (AUC) of S-warfarin by 74%.

ANALGESICS
Narcotic analgesics:
Various studies and case reports have been reviewed for rifampicin and opioid analgesics.
Rifampin 600 mg daily decreased the mean AUC for IV and oral oxycodone by 53% and 86% respectively, while oral oxycodone mean bioavailability decreased by 70%.
Rifampicin 600 mg daily reduced morphine Cmax by 41% and AUC by 28%. The analgesic effect of morphine must be monitored and morphine doses adjusted during and after rifampicin treatment.
Methadone:
Methadone is predominantly metabolized by CYP2B6 and CYP3A4.
Rifampin 600 mg daily reduced the oral bioavailability of methadone from 70% to 50%.
HORMONES AND OTHER ENDOCRINE THERAPIES
Systemic hormonal contraceptives including estrogens and progestins:
Rifampicin treatment reduces the systemic exposure of oral contraceptives.
Patients using systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control during rifampicin therapy.
Antiestrogens (e.g. tamoxifen, toremifene):
Tamoxifen and toremifen are predominantly substrates of CYP3A4.
Rifampicin 600 mg daily reduced the systemic exposure (AUC) of tamoxifen by 86% and of toremifen by 87%.
Corticosteroids:
Numerous cases appear in the literature describing a decrease in glucocorticoid effect when rifampicin is prescribed concurrently. The literature contains reports of acute adrenal crisis or adrenal insufficiency induced by the combination of rifampicin-isoniazid-ethambutol or rifampicin-isonizid in patients with Addison’s disease. In patients receiving concomitant rifampicin, prednisolone AUC was reduced by 48% to 66% and clearance was increased by 45% to 91%.
Levothyroxine:
Rifampicin 600 mg daily was administered to a patient previously treated with levothyroxine. Approximately 2 weeks after initiation of rifampicin, thyroid stimulating hormone (TSH) concentration increased by 202% compared to the pretreatment concentration. TSH concentration returned to normal 9 days after discontinuation of rifampin.
GASTROINTESTINAL SYSTEM AND BIOTRANSFORMATION
Selective 5-HT3 receptor antagonists (e.g. ondansetron):
Ondansetron is metabolized by multiple CYP enzymes.
Rifampicin 600 mg daily reduced the exposure (AUC) of orally administered ondansetron by 65% compared with placebo and the elimination half-life (t½) by 38%.
The oral bioavailability of ondansetron was reduced from 60% to 40%.
Thiazolidinediones (e.g. rosiglitazone):
Rosiglitazone is primarily metabolized by CYP2C8 and to a lesser extent by CYP2C9.
Rifampicin 600 mg daily increased rosiglitazone apparent oral clearance by 3-fold, reduced rosiglitazone exposure (AUC) by 65%, and reduced elimination half-life from 3.9 to 1.5 h.
Oral hypoglycemic agents (e.g. sulfonylureas):
Sulfonylureas are primarily substrates of CYP2C9.
Rifampicin 600 mg daily reduced the exposure (AUC) of glyburide by 39% and of glipizide by 22%, and reduced the half-life of both drugs. It is probable that the blood glucose-lowering effect of glyburide is reduced during concomitant treatment with rifampin.
ANTINEOPLASTICS
Irinotecan:
Irinotecan is extensively metabolized by various enzyme systems, including carboxylesterases, UGT, and CYP3A4.

Rifampicin 450 mg/day was administered to a patient as part of an antibiotic regimen including isoniazid (300 mg/day) and streptomycin (0.5 g/day im). Although there was no change in irinotecan exposure (AUC), irinotecan active metabolite exposure (AUC) decreased by 20% and its glucuronide metabolite decreased by 58.8%, possibly via induction of CYP3A4.
IMMUNOSUPPRESANTS
Immunosuppressive agents (e.g. ciclosporin, tacrolimus):
Ciclosporin and tacrolimus are substrates of CYP3A4 and P-gp.
In 6 healthy volunteers oral bioavailability of ciclosporin was reduced from 33% to 9% with coadministration of rifampicin 600 mg daily. In 4 kidney transplant patients, coadministration of rifampicin 600 mg daily reduced the exposure of ciclosporin (AUC) by approximately 60%.
In 6 healthy volunteers oral bioavailability of tacrolimus was reduced by 51% with coadministration of rifampicin 600 mg daily via induction of CYP3A4 and P-gp.
ANTIPARASITIC DRUGS
Praziquantel:
Praziquantel is extensively metabolized by CYP enzymes.
Rifampicin 600 mg daily reduced plasma concentrations of praziquantel to below detectable levels in 7 of 10 subjects administered single dose praziquantel; of the 3 subjects with detectable concentrations, praziquantel exposure (AUC) was reduced by 85%.
In the same study, rifampicin reduced multiple dose praziquantel concentrations below detectable levels in 5 of 10 subjects; of the 5 subjects with detectable concentrations, praziquantel exposure was reduced by 80%.
Quinine:
Quinine is mainly metabolized by CYP3A4.
Rifampicin 600 mg daily increased quinine clearance by 6.9-fold and reduced quinine exposure (AUC) and half-life.
RESPIRATORY SYSTEM
Other drugs for systemic use to treat obstructive respiratory disorders, xanthine derivatives:
Theophylline:
Theophylline is a clinical index inhibitor of CYP1A2.
Rifampicin 600 mg daily increased theophylline clearance by 40%, reduced theophylline exposure (AUC) by 27%, and reduced elimination half-life by 30%.
Effect of other medicinal products on Rifadin
Concomitant antacid administration may reduce the absorption of Rifadin. Daily doses of Rifadin should be given at least 1 hour before the ingestion of antacids.
Other drug interactions with Rifadin
When atovaquone and rifampicin were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed.
The concomitant administration of rifampicin with para-aminosalicylic acid (PAS) in formulations containing the excipient bentonite may reduce blood levels of rifampicin. The two drugs should be administered at an interval of at least 8 hours.
Interference with diagnostic and laboratory tests
Therapeutic levels of Rifadin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Thus, alternative assay methods should be considered. Transient elevation of serum bilirubin has also been observed (see section 4.4). Rifadin 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 Rifadin.
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 (e.g. Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampicin from opiates.

Pregnancy
There are no well-controlled studies with rifampicin in pregnant women.
Rifampicin has been shown to be teratogenic in rodents when given in large doses.
Although Rifadin has been reported to cross the placental barrier and appear in cord blood, the effect of the drug, 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.
Therefore, this antibiotic should be used in pregnant women or in women of childbearing potential only if the potential benefit justifies the potential risk to the fetus.
Breast-feeding
Rifampicin is excreted in breast milk. Therefore, this antibiotic should be used in a nursing mother only if the potential benefit to the patient outweighs the potential risk to the infant.
Fertility
No data are available concerning the long-term effects on human fertility.

Rifadin may cause undesirable effects which may reduce the capacity for the completion of certain tasks (see section 4.8). Patients should be informed that these undesirable effects may occur, and that if they experience these symptoms, consideration should be given not to drive or operate machinery.

The following adverse reactions are defined by System Organ Class and by frequency using 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 (cannot be estimated from the available data).
Infections and infestations
Not known: pseudomembranous colitis, influenza.
Blood and lymphatic system disorders
Common: thrombocytopenia with or without purpura, usually associated with intermittent therapy, but 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 blood clotting disorders.
Immune system disorders
Not known: anaphylactic reactions.
Endocrine disorders
Not known: adrenal insufficiency in patients with compromised adrenal function.
Metabolism and nutrition disorders
Not known: decreased appetite.
Psychiatric disorders
Not known: psychotic disorders.
Nervous system disorders
Common: headache, 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 tear color.

Vascular disorders
Not known: shock, flushing, vasculitis, bleeding.
Respiratory, thoracic and mediastinal disorders
Not known: dyspnea, wheezing, change in sputum color.
Gastrointestinal disorders
Common: nausea, vomiting.
Uncommon: diarrhea.
Not known: gastrointestinal disorders, abdominal discomfort, change in teeth color (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, pruritus, pruritic rash, urticaria, allergic dermatitis, pemphigus, change in sweat color.
Musculoskeletal and connective tissue disorders
Not known: muscle weakness, myopathy, bone pain.
Renal and urinary disorders
Not known: acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia.
Pregnancy, puerperium and perinatal conditions
Not known: post-partum hemorrhage, fetal-maternal 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: pyrexia, chills.
Not known: edema.
Investigations
Common: increased blood bilirubin, increased aspartate aminotransferase, increased alanine aminotransferase.
Not known: decreased arterial blood pressure, increased blood creatinine, increased hepatic enzymes.
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
• SFDA call center : 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Symptoms
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. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears and feces will occur, and its intensity is 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 14-60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports.
Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has 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 b.e required to control severe nausea and vomiting. Active diuresis (with measured intake and output) will help promote excretion of the drug. Hemodialysis may be of value in some patients.

Pharmacotherapeutic group: Antimycobacterials, antibiotics; ATC code: J04AB02.
Rifadin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.
Rifadin is particularly active against rapidly growing extracellular microorganisms, but it also has intracellular antibacterial activity against slow- and intermittently-growing M. tuberculosis.
It is also active in vitro against Mycobacterium avium complex, M. kansasii, and M. leprae.
Rifadin is active in vitro against a variety of gram-positive and gram-negative microorganisms. The sensitive microorganisms include Neisseria meningitidis, Neisseria gonorrhoeae, Staphylococcus aureus, Proteus spp, Staphylococcus epidermidis, H. influenzae, E. coli, Ps. aeruginosa, Legionella pneumophila, Brucella spp. and Streptococcus pyogenes. Both penicillinase-producing and non-penicillinase-producing staphylococci and beta-lactam-resistant staphylococci are susceptible to Rifadin.
Cross-resistance to rifampicin has only been shown with other rifamycins.

Absorption
Orally administered Rifadin is rapidly absorbed from the gastrointestinal tract. Peak plasma levels in adults and children vary widely from individual to individual. Peak serum concentrations of approximately 10 mcg/mL occur 2-4 hours after oral administration of a dose of 10 mg/kg body weight on an empty stomach. Absorption of Rifadin is reduced when the drug is ingested with food.
After intravenous administration of a 300 or 600 mg dose infused over 30 minutes to healthy male volunteers (n = 12), peak plasma concentrations were 9.0 and 17.5 mcg/mL respectively. The mean plasma concentration in these volunteers remained detectable for 8 and 12 hours respectively.
Pharmacokinetics (oral and intravenous) in children is similar to adults.
In normal subjects, the biological half-life of Rifadin in serum is approximately 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 mean values of approximately 2-3 hours.
At a dose of 600 mg/day, the half-life is similar in patients with renal failure and consequently, no dose adjustment is required.
Elimination
After absorption, Rifadin (oral or intravenous) is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, Rifadin undergoes progressive deacetylation, so that nearly all the drug in the bile is acetylated in 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.

Distribution
Rifadin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid.
Rifadin is about 80% protein-bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues.

Carcinogenicity
There are no human data on the long-term potential for carcinogenicity. A few cases of worsening of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when Rifadin was administered at doses 2 to 10 times the average human dose for 60 weeks followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain or in rats under similar experimental conditions.
Rifadin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro and humans.
Antitumor activity in vitro has also been shown with Rifadin.
Mutagenicity
There are no human data on the long-term potential for mutagenicity. There was no evidence of mutagenicity in bacteria, Drosophila melanogaster or mice. An increase in chromatid breaks was noted when human blood cell cultures were treated with Rifadin. Increased frequency of chromosome aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of Rifadin, isoniazid and pyrazinamide and combinations of streptomycin, Rifadin, isoniazid and pyrazinamide.

Rifadin hard capsules
Maize starch, magnesium stearate, gelatin, erythrosine (E 127), indigo carmine (E 132), titanium dioxide (E 171).
Rifadin coated tablets
Sodium laurilsulfate, microcrystalline cellulose, lactose, calcium stearate, carmellose sodium, maize starch, acacia, povidone, sucrose, talc, light magnesium carbonate, titanium dioxide, heavy kaolin, anhydrous colloidal silica, aluminum lake and erythrosine (E 127) 17%, magnesium stearate, gelatin.
Rifadin syrup
Agar-agar, sucrose, potassium sorbate, saccharin, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium metabisulphite, polysorbate 80, raspberry essence, diethanolamine, purified water.
Rifadin powder and solvent for solution for infusion
The vial of powder contains: sodium formaldehyde sulfoxylate, sodium hydroxide.
The ampoule of solvent contains: water for injections.

Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem and rifampicin (6 mg/mL in normal saline) during simulated Y-site administration. Rifadin solution for infusion must not be diluted in 5% sodium bicarbonate solution or 1/6 mol sodium lactate as precipitation may occur.
5% glucose or normal saline solutions are recommended to dilute the reconstituted solution. Use of other infusion vehicles is not recommended.

Rifadin hard capsules, coated tablets and syrup
Do not store above 25 ºC.

Box of capsules in blisters
150 mg hard capsules: 8 capsules.
300 mg hard capsules: 8 capsules.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.