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Rifampin (INN Rifampicin)

Open AccessPublished:September 29, 2015DOI:https://doi.org/10.1016/j.jpainsymman.2015.09.004
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      Off-label use
      ALT
      Alanine transaminase
      CYP
      Cytochrome P450
      FBC
      Full blood count
      IV
      Intravenous
      LFT
      Liver function tests
      LPA
      Lysophosphatidic acid
      NNT
      Number needed to treat
      PBC
      Primary biliary cirrhosis
      PO
      Per os, by mouth
      PXR
      Pregnane X receptor
      RCT
      Randomized controlled trial
      RNA
      Ribonucleic acid
      U+E
      Urea and electrolytes
      UGT
      Uridine 5’-diphospho-glucuronosyltransferase
      Class: Rifamycin antibacterial.
      Indications: Infection (notably tuberculosis and leprosy; meningococcal prophylaxis), †cholestatic pruritus.

      Pharmacology

      The bactericidal activity of rifampin is due to inhibition of bacterial RNA polymerase. Rifampin is also a pregnane X receptor (PXR) agonist, one of several receptors involved in upregulating enzymes and transporters required for the removal of xenobiotics, e.g., drugs, and endogenous metabolites, e.g., bile acids.
      • Tolson A.H.
      • Wang H.
      Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR.
      • Halilbasic E.
      • Claudel T.
      • Trauner M.
      Bile acid transporters and regulatory nuclear receptors in the liver and beyond.
      Pooled RCT data (n=61) support the efficacy of rifampin in cholestatic pruritus with an NNT of 1.75.
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      Participants had various non-cancer causes of cholestasis, mostly (80%) primary biliary cirrhosis (PBC). The RCTs were short-term (≤2 weeks), but longer-term benefit (≤2 years) has been reported.
      • Bachs L.
      • Parés A.
      • Elena M.
      • Piera C.
      • Rodés J.
      Effects of long-term rifampicin administration in primary biliary cirrhosis.
      It has been suggested that the benefit of rifampin in cholestatic pruritus is via an effect on bile acid metabolism. However, plasma concentrations of bile acids do not correlate with the severity of pruritus, nor with the response to antipruritic treatments.
      • Kremer A.E.
      • van Dijk R.
      • Leckie P.
      • et al.
      Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions.
      • Kuiper E.M.
      • van Erpecum K.J.
      • Beuers U.
      • et al.
      The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial.
      Further, other drugs with similar enzyme and transporter-inducing properties, e.g., phenobarbital, have little or no antipruritic effect.
      • Halilbasic E.
      • Claudel T.
      • Trauner M.
      Bile acid transporters and regulatory nuclear receptors in the liver and beyond.
      • Bachs L.
      • Parés A.
      • Elena M.
      • Piera C.
      • Rodés J.
      Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis.
      However, activation of the PXR receptor by rifampin also inhibits the synthesis of the enzyme autotaxin, the plasma concentration of which correlates with the antipruritic effect of rifampin. Autotaxin catalyzes the conversion of cell membrane phospholipids into the lipid signalling molecule lysophosphatidic acid (LPA), the plasma concentration of which also correlates with the severity of pruritus and falls when there is benefit from rifampin, bile acid sequestrants or biliary drainage.
      • Kremer A.E.
      • Bolier R.
      • van Dijk R.
      • Oude Elferink R.P.
      • Beuers U.
      Advances in pathogenesis and management of pruritus in cholestasis.
      How LPA causes pruritus in cholestasis is uncertain, but may include immune and/or neuro-modulation; LPA is known to affect histamine release from mast cells, eosinophil and lymphocyte trafficking, and neuronal synaptic plasticity.
      • García-Morales V.
      • Montero F.
      • González-Forero D.
      • et al.
      Membrane-derived phospholipids control synaptic neurotransmission and plasticity.
      • Yung Y.C.
      • Stoddard N.C.
      • Chun J.
      LPA receptor signaling: pharmacology, physiology, and pathophysiology.
      • Knowlden S.
      • Georas S.N.
      The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation.
      However, because levels of LPA can be increased in diseases which are not associated with pruritus, additional cofactors may be involved.
      • Jones D.E.
      Pathogenesis of cholestatic itch: old questions, new answers, and future opportunities.
      The absorption of rifampin is halved by food. Metabolites also have antibacterial effects and are excreted in bile (70%). Up to 30% of a dose is excreted in the urine, about half as unchanged drug. Half-life doubles in cirrhosis, and acute or chronic hepatitis.
      • Acocella G.
      Clinical pharmacokinetics of rifampicin.
      • Riess W.
      • Schmid K.
      • Keberle H.
      Pharmacokinetic studies in the field of rifamycins. Proceedings of the 6th International Congress of Chemotherapy.
      Bio-availability ≥95%.
      • Riess W.
      • Schmid K.
      • Keberle H.
      Pharmacokinetic studies in the field of rifamycins. Proceedings of the 6th International Congress of Chemotherapy.
      Onset of action ≥2 days (for pruritus).
      • Price T.J.
      • Patterson W.K.
      • Olver I.N.
      Rifampicin as treatment for pruritus in malignant cholestasis.
      Peak plasma concentration 2–4h.
      Plasma half-life 3–5h initially; 2–3h after repeat dosing (due to auto-induction).
      Duration of action no data for pruritus.

      Cautions

      Jaundice is listed as a warning by the US manufacturer and a contra-indication by the UK manufacturer, but rifampin was well tolerated in eight patients with jaundice and pruritus associated with hepatic metastases.
      • Price T.J.
      • Patterson W.K.
      • Olver I.N.
      Rifampicin as treatment for pruritus in malignant cholestasis.
      The risk of hepatotoxicity is increased with pre-existing hepatic impairment; monitor carefully when used for cholestatic pruritus.

      Drug interactions

      Concurrent use with isoniazid and some antiretrovirals increases the risk of serious hepatotoxicity; concurrent use of saquinavir/ritonavir is contra-indicated.
      The US manufacturer contra-indicates the concurrent use of atazanavir, darunavir, fosamprenavir, saquinavir and tipranavir, due to substantially decreased plasma concentrations which may lead to loss of antiviral efficacy and/or development of viral resistance.
      Rifampin induces various enzymes involved in drug metabolism, including oxidation (a potent inducer of CYP2B6, CYP2C19, and CYP3A4), glucuronidation (UGT1A1) and glutathione conjugation (GSTA1). Thus, caution is required with concurrent use of drugs which are metabolised by these enzymes, as rifampin may reduce their effect. Reports of interactions where close monitoring ± dose adjustment are required are listed in the Table. Onset and offset of enzyme induction is gradual, because:
      • onset depends on drug-induced synthesis of new enzyme
      • offset depends on elimination of the enzyme-inducing drug and the decay of the increased enzyme stores.
      TableClinically important cytochrome P450 interactions with rifampin
      not an exhaustive list; limited to drugs most likely to be encountered in palliative care and excludes anticancer, antiviral, HIV and immunosuppressive drugs (seek specific information).

      Baxter K, Preston CL. Stockley's drug interactions. London: Pharmaceutical Press. Available at: www.medicinescomplete.com. Accessed June 15, 2015.

      Drug effect ↓ by rifampinSpecific drugs within a class
      AnticoagulantsDabigatran
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      , rivaroxaban
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      , warfarin (and other coumarins)
      onset within one week of starting rifampin and persists for about ≤5 weeks after its withdrawal.
      AntidiabeticsCanagliflozin, gliclazide (not USA), glyburide (glibenclamide), repaglinide, linagliptin, pioglitazone, rosiglitazone (not UK), tolbutamide
      AntipsychoticsAripiprazole, haloperidol, lurasidone
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      , risperidone
      Aprepitant
      Azole antifungalsFluconazole
      generally with IV but not PO fluconazole; however, reports of therapeutic failure with PO fluconazole in patients with severe fungal infection.
      , itraconazole
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      , ketoconazole
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      , voriconazole
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      BenzodiazepinesDiazepam, lorazepam, (IV only), midazolam
      likely to be ineffective PO, avoid concurrent use; up to 60% reduction in the area under the plasma concentration-time curve for IV.
      , nitrazepam (not USA), triazolam
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      (not UK)
      BronchodilatorsAminophylline, theophylline
      Calcium channel blockersDiltiazem, nifedipine (PO only, not IV), verapamil
      CannabinoidsNabiximols
      CorticosteroidsDexamethasone, prednisolone
      Digoxin
      Doxycycline
      Fesoterodine
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      Fexofenadine
      Hormonal contraceptives
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      All, including emergency hormonal contraceptives
      Lamotrigine
      MacrolidesClarithromycin, telithromycin
      likely to be ineffective PO (and IV, where available); avoid concurrent use.
      NSAIDsCelecoxib, diclofenac, etoricoxib (not USA)
      OpioidsAlfentanil (not USA), codeine, fentanyl (all routes), methadone, morphine, oxycodone
      Phenytoin
      Ramelteon (not UK)
      Statins
      effect may increase or decrease depending on timing of administration and duration of concurrent use.
      All
      Terbinafine
      Tolvaptan
      Z-drug hypnoticsZaleplon, zolpidem, zopiclone (not USA)
      a not an exhaustive list; limited to drugs most likely to be encountered in palliative care and excludes anticancer, antiviral, HIV and immunosuppressive drugs (seek specific information).
      b likely to be ineffective PO (and IV, where available); avoid concurrent use.
      c onset within one week of starting rifampin and persists for about ≤5 weeks after its withdrawal.
      d generally with IV but not PO fluconazole; however, reports of therapeutic failure with PO fluconazole in patients with severe fungal infection.
      e likely to be ineffective PO, avoid concurrent use; up to 60% reduction in the area under the plasma concentration-time curve for IV.
      f effect may increase or decrease depending on timing of administration and duration of concurrent use.
      Thus, clinical effects may not become fully evident for 2–3 weeks after rifampin is started or discontinued.
      Conversely, some drugs may reduce the effect of rifampin:
      • antacids (reduced absorption); generally avoided by separating the administration time by ≥2h
      • phenobarbital (may increase clearance).

      Undesirable effects

      Nausea and anorexia (3% of patients with cholestatic pruritus
      • Khurana S.
      • Singh P.
      Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
      ), diarrhoea (check for Clostridium difficile toxin; pseudomembranous colitis reported), orange discolouration of sweat, saliva, urine, faeces and tears (may stain contact lenses), flushing or rash (generally mild and transient, discontinue if purpuric or urticaric).
      • Adrenal insufficiency (increased catabolism of adrenal steroids).
      • Hepatotoxicity occurs in ∼10% of patients with PBC, 1–14 months after starting rifampin.
        • Bachs L.
        • Parés A.
        • Elena M.
        • Piera C.
        • Rodés J.
        Effects of long-term rifampicin administration in primary biliary cirrhosis.
        • Prince M.I.
        • Burt A.D.
        • Jones D.E.
        Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis.
      • Hypersensitivity reactions (flu-like symptoms, urticarial, thrombocytopenia, haemolysis, renal failure) are more common with intermittent therapy used for some infections, but occurred in <2% of patients using rifampin continuously for cholestatic pruritus.
        • Khurana S.
        • Singh P.
        Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.
        Generally resolve if rifampin is stopped.

      Dose and use

      Monitoring

      Check LFTs, U+E and FBC before starting treatment and if symptoms suggestive of hepatotoxicity occur (e.g., nausea, vomiting, abdominal pain, worsening LFTs, pruritus). Repeat at intervals; there is no consensus as to frequency.
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of cholestatic liver diseases.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • et al.
      AASLD practice guidelines: primary biliary cirrhosis.
      • Saukkonen J.J.
      • Cohn D.L.
      • Jasmer R.M.
      • et al.
      ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee
      An official ATS statement: hepatotoxicity of antituberculosis therapy.
      With tuberculosis, it is recommended that rifampin is stopped if ALT increases three times the upper limit of normal (when jaundice and/or symptoms of hepatitis present) or five times (when asymptomatic).
      • Saukkonen J.J.
      • Cohn D.L.
      • Jasmer R.M.
      • et al.
      ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee
      An official ATS statement: hepatotoxicity of antituberculosis therapy.
      In cancer patients with complete biliary obstruction, worsening LFTs are inevitable, and rifampin-induced hepatotoxicity cannot be diagnosed with certainty.

      Cholestatic pruritus

      Rifampin is a second line option (see Figure):
      • start with 150mg PO at bedtime
      • if necessary, increase to 150mg twice daily after 1 week (sooner if pruritus is severe and prognosis short)
      • some patients need 600mg/24h.
      Figure thumbnail gr1
      FigAn approach to the treatment of cholestatic pruritus used in some centers
      aspecialist guidelines recommend cholestyramine for incomplete biliary obstruction, e.g., PBC.
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of cholestatic liver diseases.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • et al.
      AASLD practice guidelines: primary biliary cirrhosis.
      • Hegade V.S.
      • Kendrick S.F.W.
      • Jones D.E.J.
      Drug treatment of pruritus in liver diseases.
      Note. Because cholestyramine binds bile salts within the gut, it is ineffective in complete biliary obstruction. It is also unpalatable, and needs to be administered separately from other drugs.
      balthough experience with sertraline is limited (n=12 cross-over study in non-cancer cholestasis, mostly PBC),
      • Mayo M.J.
      • Handem I.
      • Saldana S.
      • et al.
      Sertraline as a first-line treatment for cholestatic pruritus.
      its tolerability, familiarity and limited interactions compared with rifampin generally means that it is tried first.
      cbenefit reported with androgens remains anecdotal.
      • Ahrens E.
      • Payne M.
      • Kunkel H.
      • Eisenmenger E.
      • Blondheim S.
      Primary biliary cirrhosis.
      • Lloyd-Thomas H.
      • Sherlock S.
      Testosterone therapy for the pruritus of obstructive jaundice.
      dalthough benefit confirmed in two small RCTs (n=36, mostly PBC), naltrexone (an opioid antagonist) is contra-indicated in patients needing opioid analgesia.
      • Wolfhagen F.H.
      • Sternieri E.
      • Hop W.C.
      • et al.
      Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study.
      • Terg R.
      • Coronel E.
      • Sordá J.
      • Muñoz A.E.
      • Findor J.
      Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.
      Although generally advised to take rifampin on an empty stomach to optimise absorption, when used for pruritus, strict adherence to this is probably unnecessary.
      When PO administration is not possible, the same dose of rifampin may be given by intravenous infusion (see Supply for further details).

      Supply

      Rifampin (generic)

      Capsules 150mg, 300mg, 28 [email protected] 150mg b.i.d. = $165.
      Intravenous infusion (powder for reconstitution) 600mg vial = $125.
      Reconstitute with 10mL water for injection; the displacement value of the powder may be significant, e.g., 0.48mL; consult local reconstitution guidelines. Further dilute the required dose with sodium chloride 0.9% or dextrose 5%, 100−500mL and infuse over 30min−3h respectively.

      Rifadin (Aventis Pharmaceuticals)

      Capsules 150mg, 300mg, 28 days @ 150mg b.i.d. = $200.
      Intravenous infusion (powder for reconstitution) 600mg vial = $195; see above.

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