Rifampicin

Rifampin is an Antitubercular agent belonging to mycobacterial infection.

Rifampin is used in the treatment of Meningococcal prophylaxis and Tuberculosis. It is also used to treat Anaplasmosis, symptomatic; Bartonella spp. Infections; Brucellosis; Cholestatic pruritus; Endocarditis, treatment; Hidradenitis suppurativa, moderate to severe; Leprosy; Meningococcal disease, chemoprophylaxis after close contact with a patient with invasive disease; Mycobacterial (nontuberculous) infection; Staphylococcus spp. Infections, including bone and joint and CNS; Streptococcus (group A) chronic carriage.

Rifampin is Well absorbed from the GI tract and gets widely distributed. The Volume of distribution was approx 2,000 L with plasma protein binding: ≥80%. It Crosses the placenta and is distributed into breast milk, and get metabolized hepatically by CYP2B6 isoenzyme to hydroxyRifampin as major metabolite; it may undergo extensive first-pass metabolism.

It gets excreted Via urine (mainly as metabolites, <1% as unchanged drug). Terminal plasma half-life: Approx 14 hr (immediate-release); approx 20 hr (modified-release).

The onset of Action of Rifampin was within 1-2 wk.

The Duration of Action of Rifampin was within 1-2 days.

The Tmax of Rifampin was achieved within 2 hours .Cmax was about 91 and 143 ng/mL

Rifampin shows common side effects like Hypersensitivity reactions (e.g. fever, rash, urticaria, angioedema, flu-like syndrome); superinfection (e.g. pseudomembranous colitis), anaemia, leucopenia, thrombocytopenia (with or without purpura), discolouration (yellow, orange, red, or brown) of teeth, urine.,etc.

Rifampin is available in capsules and Solution Reconstituted, Intravenous

Rifampin is available in India, Germany, Canada, Italy, USA

Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

Rifampin is available in the form of tablets and Solution Reconstituted, Intravenous.

IV: Administer IV preparation by slow IV infusion over 30 minutes to 3 hours at a final concentration not to exceed 6 mg/mL. Do not administer IM or sublingual.

May be an irritant; avoid extravasation. Restart infusion at another site if extravasation occurs.

Oral: Administer on an empty stomach (ie, 1 hour prior to or 2 hours after meals or antacids) to increase total absorption. The compounded oral suspension must be shaken well before using. May mix contents of capsule with applesauce or jelly.

Rifampin is used in the treatment of Major depressive disorder , Seasonal affective disorder and smoking cessation. It is also used to treat Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation.

Rifampin is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis.

Rifampin is approved for use in the following clinical indications

Tuberculosis: Rifampicin plays a key role in tuberculosis (TB) treatment regimens, due to its bactericidal and sterilizing capacity.

• Major depressive disorder (unipolar): Treatment of major depressive disorder (MDD)

• Seasonal affective disorder (24-hour extended release): Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD)

• Smoking cessation (12-hour extended-release [sustained release; ]): As an aid to smoking cessation treatment

• Although not approved there have been certain off label use documented for Rifampin which includes:

Attention-deficit/hyperactivity disorder; Bipolar depression; Selective serotonin reuptake inhibitor-induced sexual dysfunction, augmentation

Rifampin is available in various strengths as 150 mg, 300 mg, 600 mg

Rifampin is available in the form of capsules and Solution Reconstituted, Intravenous.

• Dosage Adjustment in Kidney Patient

CrCl >15 mL/minute: No dosage adjustment necessary.

CrCl <15 mL/minute: No dosage adjustment necessary for usual indication-specific doses ≤600 mg/day. For usual indication-specific doses ≥900 mg/day, consider limiting the dose to 600 mg/day or monitoring more closely for adverse effects except when used for meningococcal chemoprophylaxis (no adjustment necessary due to short duration of therapy).

● Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable ; no dosage adjustment necessary for usual indication-specific doses ≤600 mg/day. For usual indication-specific doses ≥900 mg/day, consider limiting the dose to 600 mg/day or monitoring more closely for adverse effects except when used for meningococcal chemoprophylaxis (no adjustment necessary due to short duration of therapy).

● Peritoneal dialysis: Not significantly dialyzable; no dosage adjustment necessary for usual indication-specific doses ≤600 mg/day. For usual indication-specific doses ≥900 mg/day, consider limiting the dose to 600 mg/day or monitoring more closely for adverse effects except when used for meningococcal chemoprophylaxis (no adjustment necessary due to short duration of therapy).

● CRRT: No dosage adjustment necessary .

● PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary.

• Dosage Adjustment in Hepatic impairment Patient

Hepatic impairment prior to treatment initiation:

There are no dosage adjustments provided in manufacturer's labeling; use with caution.

● Hepatotoxicity during treatment:

New or worsening hepatic damage: Discontinue rifampin.

• Dosage Adjustment for Pediatric Patients:

Anaplasmosis, mild, symptomatic (alternative agent):

Note: Reserve use for patients with severe allergy or intolerance to doxycycline. Rifampin is not effective for Rocky Mountain spotted fever or Lyme disease. If concurrent Lyme disease is suspected, use as part of an appropriate combination regimen.

● Infants, Children, and Adolescents: Limited data available: Oral: 20 mg/kg/day in 2 divided doses for 7 to 10 days; maximum dose: 300 mg/dose.

Brucellosis, treatment: Limited data available: Children and Adolescents: Oral: 15 to 20 mg/kg/day in 1 to 2 divided doses as part of an appropriate combination regimen; maximum daily dose: 900 mg/day. Duration is ≥6 weeks and dependent on patient-specific factors including site of infection and presence of complications.

Catheter (peritoneal dialysis); exit-site or tunnel infection: Limited data available: Infants, Children, and Adolescents: Oral: 10 to 20 mg/kg/day divided into 2 doses as part of an appropriate combination regimen. Maximum dose: 600 mg/dose . Note: Should not be used as monotherapy or routinely used in areas where Tuberculosis (TB) is endemic.

Cholestatic pruritus, persistent: Limited data available: Infants ≥4 months, Children, and Adolescents: Oral: 4 to 10 mg/kg/day in 2 divided doses; maximum daily dose: 600 mg/day . If no response, may increase dose by 2 mg/kg/day every 2 weeks to a maximum dose of 20 mg/kg/day.

Endocarditis: Use as part of an appropriate combination regimen.

Empiric therapy or culture-negative endocarditis (prosthetic valve/material):

Early (≤1 year) prosthetic valve infection or nosocomial infection associated with vascular cannulation: Children and Adolescents: Oral, IV: 20 mg/kg/day divided every 8 hours; maximum daily dose: 900 mg/day.

Late (>1 year) prosthetic valve infection: Children and Adolescents: Oral, IV: 15 to 20 mg/kg/day divided every 12 hours; maximum daily dose: 600 mg/day.

MRSA endocarditis (prosthetic valve): Infants, Children, and Adolescents: Oral, IV: 15 mg/kg/day divided every 8 hours; maximum daily dose: 900 mg/day .

● H. influenzae disease, chemoprophylaxis after close contact with a patient with invasive disease:

● Infants, Children, and Adolescents: Oral: 20 mg/kg/day once daily for 4 days; maximum dose: 600 mg/dose .

● Leprosy: Limited data available: Note: In the United States, it is strongly recommended to contact the National Hansen’s Disease Program for management of leprosy in children.

● Children and Adolescents: Oral: 10 to 20 mg/kg/day once daily; maximum dose: 600 mg/dose. If used in combination with prednisone, rifampin should be administered once monthly. Should be given as part of an appropriate combination regimen for 12 months for tuberculoid (paucibacillary) disease and 24 months for lepromatous (multibacillary) disease ; in resource-limited settings, the World Health Organization allows for shorter durations of monthly dosing for 6 months (paucibacillary) or 12 months (multibacillary)

Meningococcal disease, chemoprophylaxis after close contact with a patient with invasive disease:

● Infants, Children, and Adolescents: Oral: 20 mg/kg/day in divided doses every 12 hours for 2 days; maximum dose: 600 mg/dose.

● Mycobacterium avium complex infection: Limited data available:

● Pulmonary disease, nonsevere noncavitary nodular/bronchiectatic disease in patients without cystic fibrosis: Children and Adolescents: Oral: 15 mg/kg/dose 3 times weekly as part of an appropriate combination regimen; maximum dose: 450 mg in patients weighing <50 kg; maximum dose: 600 mg in patients weighing ≥50 kg. Note: Three-times-weekly dosing has been shown to be as effective as daily dosing in adults with mild to moderate disease with fewer adverse events.

● Pulmonary disease, severe nodular/bronchiectatic disease, cavitary disease, or disease in patients with cystic fibrosis: Children and Adolescents: Oral: 10 to 20 mg/kg/day once daily as part of an appropriate combination regimen; maximum dose: 450 mg in patients weighing <50 kg; maximum dose: 600 mg in patients weighing ≥50 kg. Note: Daily dosing is recommended in patients with cystic fibrosis due to lack of data to support intermittent dosing and uncertainty regarding absorption and lung penetration in this population.

● Duration of therapy: Continue treatment until patient is culture negative on therapy for ≥1 year.

● Peritonitis (peritoneal dialysis), treatment: Infants, Children, and Adolescents: Oral: 10 to 20 mg/kg/day divided into 2 doses in combination with other appropriate antibiotics; maximum dose: 600 mg/dose.

● Streptococcus, group A; chronic carriage: Limited data available: Note: Most individuals with chronic carriage do not require antibiotic treatment.

● Children and Adolescents:

● In combination with oral penicillin V: Oral: 20 mg/kg/day once daily for the last 4 days of treatment; maximum daily dose: 600 mg/day.

● In combination with intramuscular benzathine penicillin G: Oral: 20 mg/kg/day in 2 divided doses for 4 days starting the day of the penicillin injection; maximum daily dose: 600 mg/day .

● Tuberculosis, active (drug-susceptible); treatment :

● Note: Always administer in combination with other antitubercular drugs . Currently recommended doses in guideline, particularly those on the lower end of the range, may not achieve desired exposure . Doses of 20 to 30 mg/kg/dose have been recommended for infants and young children or for treating disseminated Tuberculosis or tuberculous meningitis.

● Initial intensive phase: Note: Administer part of a standard 4-drug regimen for 2 months.

● Infants, Children, and Adolescents <15 years weighing ≤40 kg: Oral, IV: 10 to 20 mg/kg/dose once daily (or 5 days/week by directly observed therapy); maximum dose: 600 mg/dose.

● Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IV: 10 mg/kg/dose once daily (or 5 days/week by DOT); maximum dose: 600 mg/dose.

● Continuation phase: Note: Administer in combination with isoniazid for ≥4 months; continuation phase duration should be longer for cavitary disease with positive cultures at completion of intensive phase (7 months), bone and joint disease (≥4 to 7 months), and CNS disease (7 to 10 months).

● Infants, Children, and Adolescents <15 years weighing ≤40 kg: Oral, IV: 10 to 20 mg/kg/dose once daily (or 5 days/week by DOT); maximum dose: 600 mg/dose.

● Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Oral, IV: 10 mg/kg/dose once daily (or 5 days/week by DOT); maximum dose: 600 mg/dose.

● Alternative dosing intervals: Daily or 5-times-weekly dosing is preferred, particularly during the intensive phase and in patients with HIV. If neither is feasible, alternatives in order of preference are: Daily (or 5-times-weekly) dosing for the intensive phase followed by 3-times-weekly dosing during the continuation phase; 3-times-weekly dosing for the duration of treatment; and daily dosing for 2 weeks followed by twice-weekly dosing. Twice-weekly dosing should not be used in patients with HIV, who are smear-positive, or who have cavitary disease. Directly observe therapy for any regimen that is <7 days/week dosing.

● Tuberculosis, latent infection; treatment: Infants, Children, and Adolescents: Independent of HIV status: Oral: 15 to 20 mg/kg/day once daily; maximum dose: 600 mg/dose; use in combination with isoniazid for 3 months or as monotherapy for 4 months . Higher doses of 20 to 30 mg/kg/dose have been recommended for infants and young

Limit intake of refined carbs such as maida and sugar-laden foods as they offer only empty calories devoid of nutrients.

Deep-fried foods and junk foods packed with saturated fats and trans-fat would worsen symptoms associated with TB, such as diarrhoea, abdominal cramps, and fatigue.

Totally steer clear of alcohol during the entire period of treatment, as it can interfere with treatment and may result in side effects.

Avoid taking excessive caffeine and carbonated beverages.

Hypersensitivity to rifampin, any rifamycins, or any component of the formulation; concurrent use of atazanavir, darunavir, fosamprenavir, praziquantel, ritonavir/saquinavir, saquinavir, or tipranavir.

Disease-related concerns:

• Diabetes mellitus: Use with caution in patients with diabetes mellitus; management of diabetes may be more difficult in patients taking rifampin.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Meningococcal disease: Do not use for treatment of meningococcal disease, only for short-term treatment of asymptomatic carrier states.

• Porphyria: Use with caution in patients with porphyria; exacerbations have been reported due to enzyme.

Rifampin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Rifampin is present in breast milk.

Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. Breastfeeding is not a contraindication during therapy for drug-susceptible Tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, rifampin). Exposure to rifampin via breast milk should not be considered effective treatment for the breastfeeding infant

Pregnancy Category C

Rifampin has been shown to be teratogenic in rodents. Congenital malformations, primarily spina bifida, were increased in the offspring of pregnant rats given rifampin during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area comparisons).

• Common Adverse effects

Hypersensitivity reactions (e.g. fever, rash, urticaria, angioedema, flu-like syndrome); superinfection (e.g. pseudomembranous colitis), anaemia, leucopenia, thrombocytopenia (with or without purpura), discolouration (yellow, orange, red, or brown) of teeth, urine, sweat sputum, tears.

• Less Common Adverse effects:

Mental confusion, behavioural changes, inability to concentrate.

• Rare Adverse effects

Headache, dizziness, drowsiness, generalised numbness.

• May increase the risk of hepatotoxicity when given with halothane or isoniazid. May decrease the serum concentrations, thus reducing the efficacy of praziquantel. May enhance the adverse effect, particularly bleeding, when given concomitantly with cefazolin and other cephalosporins containing N-methylthiotetrazole side chain. May increase metabolism and decrease serum concentrations and effects of antiarrhythmics (e.g. disopyramide, quinidine), antiepileptics (e.g. phenytoin,), barbiturates, hormone antagonist (e.g. tamoxifen, toremifene), antipsychotics (e.g. haloperidol, aripiprazole), anticoagulants (e.g. warfarin), antifungals (e.g. fluconazole, ketoconazole), other antiretrovirals (e.g. zidovudine, indinavir, efavirenz), hepatitis C antiviral drugs (e.g. daclatasvir), beta-blockers (e.g. bisoprolol), Ca channel blocker (e.g. diltiazem), anxiolytics and hypnotics (e.g. diazepam), certain antibacterials (e.g. chloramphenicol, clarithromycin), corticosteroids, cardiac glycosides, hormonal contraceptives (e.g. oestrogens, progestogens), antidiabetic agents (e.g. glipizide, rosiglitazone), immunosuppressants (e.g. ciclosporin, tacrolimus), thyroid hormone (e.g. levothyroxine), analgesics (e.g. methadone, morphine), selective 5-HT3 receptor antagonists (e.g. ondansetron), statins that are metabolised by CYP3A4 (e.g. simvastatin), TCAs (e.g. amitriptyline, nortriptyline), cytotoxics (e.g. imatinib), enalapril, losartan, irinotecan, theophylline, quinine, riluzole. Absorption may be reduced by antacids. Concomitant use with atovaquone increased plasma concentrations of rifampicin and decreased plasma concentrations of atovaquone. Increased plasma concentrations with probenecid and trimethoprim-sulfamethoxazole.
• Potentially Fatal: Increased risk of severe hepatotoxicity with saquinavir/ritonavir combination. It may substantially decrease the plasma concentrations and efficacy of atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir which may result in the development of viral resistance.

The common side effects of Rifampin include the following

Constipation, Diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Symptoms: Nausea, vomiting, abdominal pain, pruritus, headache, lethargy; unconsciousness (in presence of severe hepatic disease); transient increases in liver enzymes and bilirubin; brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, faeces; facial or periorbital edema (particularly in children); liver enlargement, hypotension, sinus tachycardia, ventricular arrhythmias, seizures, cardiac arrest.

Management: Supportive and symptomatic treatment. Secure airway and establish an adequate respiratory exchange. Perform gastric lavage within 2-3 hours of ingestion to induce emesis followed by instillation of activated charcoal into the stomach. May administer antiemetic agents to control severe nausea and vomiting. May consider active diuresis, with measured intake and output, to promote excretion. For severe cases, hemodialysis may also be considered.

Pharmacodynamic

Rifampin is thought to inhibit bacterial DNA-dependent RNA polymerase, which appears to occur as a result of drug binding in the polymerase subunit deep within the DNA/RNA channel, facilitating direct blocking of the elongating RNA. This effect is thought to be concentration related .

Pharmacokinetics

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Rifampin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Rifampin
• https://europepmc.org/article/med/6988203