TOP 10 Clinically Significant Drug-Drug Interactions What Every

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TOP 10 Clinically Significant Drug-Drug Interactions What Every Powered By Docstoc
					   Top 10 Drug-Drug Interactions
         to Avoid (or NOT):
       What Every Clinician
           Needs to Know

                      Betty J. Dong, PharmD,
                Professor of Clinical Pharmacy
             University of California San Francisco

                                                                                The International AIDS Society–USA
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
  Common Interacting ARV-Drugs/Classes
  Acid Reducing Agents                                             Ergots
  Azole Antifungals                                                Gout drugs
  Antimycobacterials                                               Herbals
  Anti-epileptic agents                                            Immunosuppressives
  Anti-depressants                                                 Macrolides
  Asthma agents                                                    Methadone
  Benzodiazepines                                                  Oral contraceptives
  Cardiac medications                                              Pimozide
  Chemotherapeutic agents                                          Pulmonary hypertension drugs
  Erectile dysfunction                                             Statins
  Ectasy/illicit drugs                                             Warfarin

From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
        Maraviroc (MVC) Drug Interactions

      MVC is 3A4 and Pgp substrate
      3A4/pgp inhibitors (e.g. azoles, PI, delavirdine,
       macrolides)
        MVC AUC/toxicity

      3A4/pgp inducers (e.g. NNRTI, anticonvulsants,
       rifamycins)
         MVC AUC/efficacy

      Strong inhibitors overcome effects of inducers


From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
                     Maraviroc-ARV Interactions
ARVs                                            MVC Interaction                          MVC Dose

All PI (except TPV/r)                          MVC AUC                                  150 mg bid
and DLV

NNRTI: EFV, ETR                                 MVC AUC                                 600 mg bid
(except NVP, DLV)

PI + NNRTI                                      MVC AUC                                 150 mg bid
(except TPV/r, NVP)

NRTI                                           none                                      300 mg bid

RAL, NVP, TPV/r,                               none                                      300 mg bid
T-20


From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
           Etravirine (ETR) Drug Interactions with
                   Protease Inhibitors (PI)
   ETR: 3A4, 2C9 and 2C19 substrate
      Moderate 3A4 inducer

      Moderate inhibitor of CYP2C9, CYP2C19, pgp

   AVOID ETR with:
      Tipranavir/r              ETR levels
      Fosamprenavir/r          APV levels 69%
      Atazanavir/r             ATV levels 38%
                                 ETR levels 100%
      Any unboosted PI:         ATV and IDV levels,
                                 APV/ NFV
Scholler-Gyure M, Kakuda T. 49th ICAAC, 2009, Abst A1-1298
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
                  Etravirine (ETR) Administration with
                         Protease Inhibitors (PI)
   Cautious co-administration of ETR with:
    (Ok with twice daily “SaLoD”)

         LPV/r TABS                                                               ETR levels 30-45%
          400/100 mg bid                                                            LPV 15-30% (NS)

         SAQ/r                                                                    ETR levels 33%
          1000 mg/ritonavir 100 mg bid

         DRV/r                                                                    ETR AUC 37%,
          600 mg bid plus                                                           Cmin 49%
          ritonavir 100 mg bid                                                     (effective DUET)
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
Atazanavir and H2 Antagonists in Treatment-
               Naïve Persons
     ATV 300 mg/r 100 mg
        Administer simultaneously with and/or >10 hr after
         the H2-antagonist
        Do not exceed 40 mg BID of famotidine or equivalent
         (300 mg bid ranitidine, 800 mg bid cimetidine, 300 mg
         bid nizatidine)
     Unboosted ATV 400 mg/day
        Give ATV 2 hr before or 10 hr after H2 blocker
        Do not exceed 20 mg BID daily of
         famotidine/equivalent (ranitidine 150 mg bid,
         cimetidine 400 mg bid, nizatidine 150 mg bid)
                                             FDA Update 9/30/08, ATV package insert 4/2010
From BJ Dong, PharmD, at   13th   Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
     Atazanavir for Treatment-Experienced Persons


     H2 antagonist should not exceed dose equivalent of
      famotidine 20 mg BID
        Administer ATV 300 mg/RTV 100 mg simultaneously
         with, and/or >10 hr after the H2-antagonist.

     ATV 400 mg/RTV 100 mg once daily
        if taken with both tenofovir and H2-antagonist




From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
             Atazanavir and Proton Pump Inhibitors
    Use PPI only in treatment-naïve persons
          Avoid >20 mg/day of omeprazole
          Take PPI 12 hours before ATV 300/r 100 mg
    Avoid PPI with unboosted ATV
    Avoid PPI in treatment-experienced persons

ATV dose                                          OMP Dose                               Cmin
ATV/r 300/100 mg daily                            40 mg/day                              ↓ 78%
                                                  20 mg/day                              ↓ 46%

ATV/r 400/100 mg daily                            20 mg/day                              ↓ 31%
                                     FDA Update 9/30/08, Reyataz package insert 4/2010
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
  Anticonvulsants To Avoid with ARVs
3A4 substrates                     PI Interaction                     NNRTI                      Comments
and inducers                                                          Interaction
Phenytoin (2C9)                    PIlevels (except                   NNRTI                    Avoid -risk of
(PHT)                              FPV/r)                                                        virologic failure
                                    PHT levels                                                  except FPV/r
Carbamazepine                      PIlevels (except                  NNRTI                     Avoid -risk of
(CBZ)                              DRV/r)                             CBZ                       virologic failure
                                    CBZ toxicity                                                except DRV/r

Oxcarbazepine                      PI   levels                       NNRTI levels              Avoid -risk of
                                                                                                 virologic failure


Phenobarb                          PIlevels                          NNRTI                     Avoid -risk of
(PB)/Primidone                      PB levels                         PB levels                virologic failure and
                                    PB w/ TPV/r                                                 PB toxicity


From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
Summary: Anticonvulsants and ARVs
   Avoid P450 enzyme inducing anticonvulsants that can  PI
    and NNRTI levels and  risk of anticonvulsant toxicity
   Change to anticonvulsants with low risk of PI/NNRTI
    interactions
      Levetiracetam

      Gabapentin

      Pregablin

      Vigabatrin: risk of visual field defects

      Lamotrigine and valproic levels  by LPV/r

   Changes require tapering one anticonvulsant while
    increasing the other to avoid seizures.
   Monitor anticonvulsant/PI/NNRTI levels
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
Antihyperlipidemics-PI/NNRTI Interactions
     Statins metabolized by CYP3A4
           Simvastatin, lovastatin >>atorvastatin> rosuvastatin,
            pitavastatin, pravastatin, fluvastatin
     NNRTIs (EFV, ETR, NVP)
            statin levels 40%
            statin dose for efficacy
     PI inhibit statin metabolism/ statin levels/toxicity
           Simvastatin/lovastatin C/I:  AUC 500%-3059%
            risk of myopathy/rhabdomyolysis
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
        Antihyperlipidemics-PI Interactions
     Atorvastatin:  AUC 70 to 836% with all PI’s
         AUC 500% to 836% with LPV/r and TPV/r

        DRV/r: 10 mg atorvastatin = 40 mg/day

        Start with 10 mg/day and titrate upward

        Rhabdomyolysis/myopathy reported

     Rosuvastatin:  AUC 26-213% (ATV/r, LPV/r)
        No interaction observed with FPV +/- ritonavir

        Start with 5 mg/day, titrate up to 40 mg/day

     Pravastatin:  AUC 81% with DRV/r--start with 10
      mg/day and titrate upward
     Pitavastatin:  AUC 30%+ with ATV; C/I w/ LPV/r
     Fluvastatin: not 3A4 metabolism
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
                                   Why Fluticasone??
    Metabolized by 3A4, inhibitors  fluticasone levels and
     depress cortisol
     fluticasone AUC 350-fold with RTV 100 mg q 12 hr
     and 200 mcg intranasal fluticasone PK
    Greater likelihood of systemic accumulation
       33 cases fluticasone and adrenal insufficiency without
        3A4 inhibitors
    Avoid other strong 3A4 inhibitors (e.g. diltiazem,
     itraconazole, clarithromycin).
    Lowest dose/duration of inhaled/intranasal steroids
    Consider montelukast or less potent steroids:
     triamincinolone, beclomethasone
    Replace PI component if feasible
HIV Medicine (2008) 9, 389–396; Eur J Clin Pharmacol. 2009 Jul;65(7):743-5; Micromedex
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
         Protease Inhibitors and Salmeterol
    Administration salmeterol and PI not recommended
    Risk of  salmeterol concentrations,
    Risk  QTc duration, palpitations, sinus tachycardia, and
     CV complications
    Theoretical interaction with PI
    Salmeterol metabolized by 3A4 isoenzymes
    Ketoconazole 400 mg/day plus salmeterol 50 mcg bid X 7
     days →16-fold  in salmeterol AUC and a significant 1.4-
     fold increase in salmeterol Cmax
          (N=20), 2 w/ QT, 3 D/C d/t ADR, 1 sinus tach
    Consider formoterol
http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm209920.ht
    mProd Info salmeterol inhalation powder, 2008); Micromedex Drug Information
From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
                     Antidepressants and ARVs
    Trazodone: metabolized by 3A4
       RTV 200mg BID  trazodone AUC 240%

       Use lowest trazodone; monitor for CNS and CV
        adverse effects
    SSRI:  SSRI dose based on clinical response
       Sertraline:  AUC/Cmin 40-50% w/DRV/r, EFV

       Paroxetine: AUC/Cmin 39%,  free levels
        25-35% by DRV/r,  AUC 55% by FPV/r
    Bupropion: (2B6 metabolism)  dose prn
       AUC  55% by EFV

       AUC  50-60% by LPV/r, TPV/r
                                                                                          J. Clin Pharmacol 2003;43:414
From BJ Dong, PharmD, at   13th   Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
                       Benzodiazepines and ARVs
Drug                    ARV                         Interaction                           Comment

Alprazolam              RTV 200 mg                  alprazolam AUC                       Contraindicated ???
                        BID X 2 days                248%


Triazolam               RTV 200 mg                   triazolam AUC                       Contraindicated with PI ?
                        BID                         2000%.


Midazolam               SQV/r                        midazolam (oral) PI and NNRTI C/I with
                                                    AUC 1,144%         oral midazolam. Single
                                                                       IV dose ok

Diazepam                ETR                          diazepam                            Monitor and reduce
                        PI                          possible                              diazepam dose prn


Use lorazepam, oxazepam, temazepam
 From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.   JAIDS 2000;24:129-36
       Calcium Channel Blockers and PI/NNRTI
                   Interactions
   Verapamil and diltiazem are 3A4 substrate/inhibitors
      ATV/r diltiazem AUC 125%
       diltiazem 50% with ATV/r to avoid  PR
      Monitor for CV toxicity
      EFV/NVP  diltiazem/CCBs
   Dihydropyridines (e.g. amlodipine, felodipine)
      Wide therapeutic and toxic levels
      Monitor for hypotension with PI
      Monitor for reduced efficacy with NNRTI
      No dosage adjustments recommended

From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
 Alpha Blockers and Protease Inhibitors
    Co-administration with alfuzosin contraindicated
    Theoretical:
       Alfuzosin is a 3A4 substrate

       Ketoconazole, a strong 3A4 inhibitor, resulted in 2 to
        3-fold increases in alfuzosin Cmax and AUC values
        after a single dose of alfuzosin
        alfuzosin levels may  risk of hypotension

    Avoid tamulosin – also 3A substrate
    Others (prazosin, terazosin, doxazosin) are not 3A4
     substrates
Prod Info alfuzosin extended release oral tablets, 2010, Micromedex

From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
     Erectile Dysfunction Agents and Protease
                     Inhibitors
    Use these agents cautiously at reduced doses
    Monitor for adverse CV events
    Sildenafil of 25 mg every 48 hours
       DRV/r + 25 mg sildenafil = 100 mg sildenafil alone

       ETR may  sildenafil and higher doses needed

    Tadalafil 5 mg initially, max of 10 mg every 72 hours
    Vardenafil
       2.5 mg initially every 72 hours

       2.5 mg every 24 hours with unboosted ATV

From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.
    Pulmonary Arterial Hypertension—
    NEW Recommendations With ALL PI
     Phosphodiesterase inhibitors:  with 3A4 inhibitors
     Sildenafil is contraindicated: risk of hypotension
     Tadalafil 20 mg/day initially,  to 40 mg/day as needed if
      taking PI for 1 wk
        If on tadalfil, stop tadalafil 24 hr before and for 1 week
          after starting PI. Resume tadafafil 20 mg/day, max 40
          mg/day (exceptions NFV and IDV)
     Bosentan 62.5 mg/day or QOD if on PI X 10 days
        If on bosentan, stop bosentan 36 hr before and for at
          least 10 days after starting PI (except NFV/ IDV)
        Avoid co-administration with unboosted ATV
    From BJ Dong, PharmD, at 13th Annual Ryan White HIV/AIDS Program Clinical Conference, IAS–USA.

				
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