DRUG NAME: RIFAMPIN

STATUS OF DRUG:

1)(WHO) ESSENTIAL DRUG LIST: ( Exist)

2)NATIONAL ESSENTIAL DRUG LIST: (Exist)

PRODUCT DESCRIPTIONS:

SR NO

BRANDS MANUFACTURERS

DOSAGE FORM & DESIGN

PACK SIZE PRICE/UNITIN RUPEES

1 Rifinah(300)mg

1)INH=75mg

2)RMP=150mg

Pacificpharmaceutical

Tablets(300)Mg (3×10)=30 Rs:257

2 Myrin(600)mg1)EMB=300 mg2)INH=75mg3)RMP=150mg

Wyeth pharmaceuticalPak(ltd).

Tablets(600)mg (8×10)=80 Rs:629

3 Rimactal Novartis pharma(pak)ltd

1)Capsule(300mg) 2)Tablet(450mg)3)Syrup( 20mg/ml)

(4×10)=40(10×3)=3060 ml

Rs:243Rs:282Rs:70

4 Rifatol1)RMP=150mg2)INH=75mg3)EMB=300mg

SChazoo zaka PharmaceuticalPvt).

Tablet(600)mg

10×10) Rs:786

5 MYRIN-P( FORT)1)EMB=275mg2)RMP=150mg3)INH=75mg4)PZA=400mg

Wyeth pharmac euticalPak(ltd).

Tablet (10×8)=80 Rs:875

STORAGE: 1) store at temperature not exceeding 25°c in an atmosphere of nitrogen in air tight container. 2) Protect from light.

CHEMISTRY OF THE PRODUCT

CHEMICAL CLASS CHEMICAL STRUCTURE PHYSICAL PROPERTIES

4-methyl-1-piperazinaminyl group,

1)Rifampicin is a reddish brown crystalline powder2)slightly soluble in water ,alcohol and in acetone and soluble in methyl alcohol.

CHEMICAL PROPERTIES1)Melting point:(183–188) °C2)1%SUSPENSION PH=4.5-6.53) Molecular mass: 822.94 g/molFormula: C43H58N4O12

PHARMACOKINETICS :A)ABSORPTION:

Orally administered rifampicin results in peak plasma concentrations in about ( 2 -4) hours.Rifampicin is easily absorbed from the gastrointestinal tract; its ester functional group is quickly hydrolyzed in the bile, and it is catalyzed by a high pH and substrate-specific enzymes called esterases. After about six hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and it is subsequently eliminated from the body. . When rifampicin is taken with a meal, peak blood concentration falls by 36%.

B)DISTRIBUTION:

Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the CSF . Since the substance itself is red, this high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces.

BIOAVAILABILITY

%PROTEIN BINDING

PLACENTAL BARRIER

BBB SECRETIONIN MILK

VOLUME OFDISTRIBUTION

TIME OF ONSET OFACTION

THERAPEUTICSERUM LEVEL

90 – 95)%

80 -90)%

rifampin has been reported to cross the placental barrier and appear in cord blood,

The combination of isoniazid and rifampicin for 1 year, with appropriate management increases theintracranial pressure.

RIFAMPINexcreted during lactation, relatively safe in the minimal quantities ,nursing infants ingest through breast milk.Rifampin may harm a nursing baby.

The apparent volume of distribution is1.6 L/Kg in adults and 1.1L/Kg in children.

(2-3)h

Rifampicin therapeutic levels( 7-10) Microgram/ml are attained after 2-3 hours.

C)ELIMINATION:

Only about( 4-20)% of the administered drug will be excreted unchanged through the urine, though urinary elimination accounts for only about 20% of the drug excretion.Rifampin is excreted mainly through liver into bile,then undergoes enterohepatic recirculation with the bulk excreted as a deacylated metabolite in feces About 60% to 85%.

Elimination half life

Site of metabolism Active metabolites Route of excretion

Elimination half life increases with increasing dosesand amounts to 2.5h,3.5h,and about 5h after single doses of 300mg,600mg and900mg respectively.

Rifampin is metabolized in the liver.

principal active metabolite is deacetylrifampicin

Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and (6 to 30)% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Approximately( 43- 60)% of oral dose is excreted in the faeces.

CLINICAL PHARMACOLOGY1)THERAPEUTIC CLASS: Antituberculosis

2)PHARMACOLOGICAL CLASS: rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis mediterranei and Streptomyces mediterranei).

3)MECHANISM OF ACTION: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

4)SPECTRUM: ( broad spectrum bactericidal)

the most susceptible bacteria are:

1) Aerobic Gram-Negative Microorganisms

Neisseria meningitidis

Mycobacterium tuberculosis

2)Aerobic Gram-Positive Microorganisms

Staphylococcus aureus (including Methicillin-Resistant S. aureus/MRSA)Staphylococcus epidermidis

3)Aerobic Gram-Negative Microorganisms

Haemophilus influenzae

4)“Other” Microorganisms

Mycobacterium leprae

5)INDICATIONS:

Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and Hansen's disease (Leprosy). Rifampicin is used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid , including in difficult to treat infections such as osteomyelitis and prosthetic joint infections.It is

also used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection.

It is also used to treat infection by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila

6A)CONTRAINDICATION :

Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity.

Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

6B)PRECAUTIONS:

Rifampin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases.

Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D.

7)POSSIBLE SIDE EFFECTS:

Headache,drowsiness,dizziness,numbness,thrombocytopenia,

Eosinophilia,leukopenia,hemolyticanemia,epigastric distress,

Nausea,vomiting,anorexia,skin allergy.

8) ADVERSE REACTIONS:

A)Hepatic

Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkaline phosphatase, serum transaminases) have been observed.

B)Hematologic

Rare reports of disseminated intravascular coagulation have been observed.

C)Central Nervous System :Psychoses have been rarely reported.

D)Endocrine Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

E)Renal Acute tubular necrosis

F)Hypersensitivity Reactions; Erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis,vasculitis. Anaphylaxis has been reported rarely.

G)Gastrointestinal : Pancreatitis

H)Hypersensitivity Reactions:( Stevens-Johnson syndrome)

Dosage and administration:

Sr no

indications Route of administration

Neonates/infants mg/kg/day frequency

Child mg/kg/dayfrequency

Adult mg/kg/day

Duration of therapy

1 Rifampicin is recommended during the initial initial intensive phase of short courseTreatment of tuberculosis which usually lasts two months on a daily basis. Rifampicin and INH for initial intensive phase .

Oral route 5mg/kg daily in two divided doses.60 ml syrup (20mg/ml)

10mg/kgDaily in two divided doses.

600mg-1200mg daily in two divided doses.

6-8 months therapy WithRMP+INH+PZA ANDEMB)

Administration guidelines:

A)for oral route:

To ensure optimum absorption of oral rifampicin should preferably be taken on an empty stomach,at least ½ h before a meal.syrup should be well shaken before use.

B)For I/V Route:

PREPARATION of Solution for IV Infusion : Reconstitute the lyophilized powder by transferring 10 mL of

sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for 24 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

STABILITY: Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

FOOD-DRUG INTERACTION: Food delays and reduces the absorption of rifampicin from the gut:

Clinical evidence: The absorption of a single 10-mg/kg dose of rifampicin was reduced when it was given to 6 healthy subjects with a standard Indian breakfast (125 g wheat, 10 g visible fat, 350 g vegetables). The AUC after 8 hours

was reduced by 26% and the peak plasma levels were prolonged (from

11.84 micrograms/mL at 2 hours to 8.35 micrograms/mL at 4 hours) and

reduced by about 30%.1 In another study, a high-fat breakfast reduced

the maximum serum level of rifampicin 600 mg by 36% and delayed the

absorption, but the AUC was not significantly altered.

Mechanism: Not understood.

Importance and management: Rifampicin should be taken on an empty stomach (at least 30 minutes before a meal, or 2 hours after a meal) to

ensure rapid and complete absorption.

DRUG-DRUG INTERACTIONS;interactions Significance

leveloutcome Mecha-

nismRecomme-ndation

ACE-inhibitors(enalapril)+Rifampin

Onset=rapidSeverity=moderateDocumentation=possible

Phamacological effects of enalapril may decrease.

unknown

Consider monitoring of B.P in patients that are receiving combination therapy.if B.P increases alternative antihypertensive therapy is recommended.

Aminophylline+rifampin

Onset= delaySeverity=moderateDocument=established

Phamacological levels of aminophylline may decrease with increase exacerbation of pulmonary symptoms.

Increased hepatic metabolism via enzyme induction of rifampin.

Addition or deletion of rifampin therapy.

Beta blockers(propranolol)+rifampin

Onset=delaySeverity=moderateDocument=probable

Beta blocker effects may be reduced via rifampin.

Increased hepatic metabolism from enzyme induction via rifampin.

Consider monitoring of B.P in patients that are receiving combination therapy.if B.P increases alternative antihypertensive therapy is recommended.

BARBITURATES( phenobarbitol,pentobarbital,Amobarbitol,Butabarbitol)+ rifampin

Onset=delaySeverity=minimDocument=possible

May result in increase rate of metabolism of barbiturates and reduce its pharmacological actions.

Rifampin may stimulate microsomal enzyme and increase degradation of barbiturate.

Barbiturate plasma level is monitored and dosage mey need to increase.

interaction Significant level outcome mechanism recomendationContraceptives+rifampin

Onset= delaySeverity=moderateDocument=established

May decrease oral contraceptive efficacy and also may

Rifampin induces hepatic microsomal enzymes that

Advise patient to use an additional form of contraceptive in rifampin

increase incidences’ of menstrual abnormalities.

may result in more rapid elimination of estrogenic and progestational components of oral contraceptives.

therapy.

Quinine derivatives+rifampin

Onset=delaySeverity=moderateDocument=establish

May increase metabolism of quinine derivatives that may be associated in reduction in therapeutic effects.

Rifampin is potent inducer of hepatic microsomal enzymes that may increase the hepatic clearance of quinine derivatives.

Advise patient to increase dosage of quinine derivaties to maintain therapeutic effects.

Drug/Laboratory Interactions 1)Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen On Line opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish rifampin from opiates.

2)Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been

observed. Therefore, these tests should be performed before the morning dose of rifampin.

Rifampin in pregnancy: FDA pregnancy category C. This medication may be harmful to an unborn baby. Rifampin has been shown to be teratogenic in rodents given oral doses of rifampin 15 to 25 times the human dose. Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs on the human fetus is not known. Neonates of rifampin-treated mothers should be carefully observed for any evidence of adverse effects. Isolated cases of fetal malformations have been reported; however, there are no adequate and well-controlled studies in pregnant women. Rifampin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy-Non-Teratogenic Effects:When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Nursing Mothers: Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Toxicology: (OVERDOSAGE)Signs and Symptoms: Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within a short time after 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.Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Acute Toxicity: The LD50 of rifampin is approximately 885 mg/kg in the mouse, and 2120 mg/kg in the rabbit.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 gm rifampin. Fatal acute overdoses in adults have been reported with doses ranging from 14- 16gm.

Treatment:The airway should be secured and adequate respiratory exchange established. Since nausea and vomiting are likely to be present, gastric lavage within the first 2 to 3 hours after ingestion is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

REFRENCES:1)Basic and clinical pharmacology by katzung(11th edition)

2) http:/www.medincell.com

2) drugs interactions facts via Davis.Tatro(4th edition)

3) http:/www.medincell.com

4) Pharmacology (Lippincott's Illustrated Reviews Series) [Richard A. Harvey PhD, Michelle A Clark PhD, Richard Finkel PharmD.

5) www.fda.gov/Food/default.htm .

6) www.pharmaguideindia.com/.