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Drug-Drug Interactions

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Kirsten Balano

on 20 May 2015

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Transcript of Drug-Drug Interactions

Interactions Among ARV Agents
NRTI Interactions:
Tenofovir/Atazanavir : lowers atazanavir levels
MUST BOOST WITH RITONAVIR
Didanosine significant interactions: PK and increased toxicity - AVOID USE!
Searching for Interactions
www.hivdrug-interactions.org
Framework for Evaluating Drug Interactions
1. OBTAIN complete medication history
2. SEARCH for definate vs probable vs theoretical interactions
Pharmacokinetic
Pharmacodynamic
3. ASSESS clinical significance of interactions

4. MANAGE/MONITOR interaction
5. EDUCATE patient/provider
Antacids and ARV Agents
Atazanavir & Rilpivirine: Require acidic pH for effective absorption.
Tuberculosis and ARV Agents
HIV and Tuberculosis are common co-infections
Erectile Dysfunction Agents and ARV
Kirsten B. Balano, PharmD, AAHIVP
CP131-Feb 2013

HIV Drug-Drug Interactions
CYP450 Mediated
Absorption
Elimination (Renal)
Antagonism
Additive Toxicities
TIMING
Lexicomp
Micromedix
www.aidsinfo.nih.gov
NNRTI/PI:
NNRTI CYP3A4 inducers & substrates
PI CYP3A4 inhibitors and substrates
Nevirapine>Efavirenz>Rilpivirine for enzyme induction
COBI/PI: No clear data
DO NOT COMBINE
Statins and ARV Agents
Antiepileptic Drugs and ARV Agents
Methadone and ARV Agents
Likely not CYP related
Cases:
Case 1:
38 yo man newly diagnosed with HIV and Tuberculosis
CD4 Count: 90
HIV VL: 130,000
Wt: 65kg
Starting 4 drug TB Therapy:
Rifampin 600mg Daily
Isoniazid 300mg Daily
PZA 1500mg Daily
Ethambutol 1200mg Daily
Vit B6 50mg daily

?Which of the preferred ARV Regimens would you recommend?
PI Boosting:
Improves exposure for active PI, decrease dose frequency. Preferred method for dosing.
Rifampin - potent CYP3A4 inducer - ?What are challenges?
Avoid Rifamycins with EVG/COBI/TDF/FTC
What medications are commonly started upon admission to hospital?
Separate EVG/COBI/TDF/FTC by more than 2 hours from bivalent cation antacids
Boosted PI may DECREASE (?) methadone levels

PK studies confirmed methadone AUC decreased 16-53% and cases of withdrawal symptoms.
NNRTI: Efavirenz and Nevirapine more significantly decrease methadone levels than PI
Etravirine and Rilpivirine minimal effects expected
Integrase Inhibitors (even EVG/COBI) no dose adjustment recommended
Maraviroc - No Data
Statins are Substrates of CYP 3A:
Simvastatin/Lovastatin>>rosuvastatin>atorvastatin>pravastatin
AVOID Simvastatin, lovastatin and pitavastatin with Protease Inhibitors (especially boosted) and Elvitegravir/Cobicistat
Start with lowest doses of atorvastatin, rosuvastatin and pravastatin and titrate to response
Pravastatin levels significantly increased with darunavir/ritonavir (avoid vs low dose of low potency statin?)
Carbamazapine, phenobarbitol, phentyoin: CYP3A inducers and substrates

Bidirectional drug interactions
Levetiracetam safest antieplieptic to use with PI/NNRTI
Raltegravir safest ARV to use with AEDs
ED agents CYP3A substrates
Protease Inhibitors and COBI significantly increase ED Concentrations
Use lowest starting dose & monitor for toxicities:
Sildenafil: start 25mg Q 48 hours
Vardenafil: start 2.5mg Q 72 hours
Tadalafil: start 5mg (NTE 10mg Q72hr)
Oral Contraceptives and ARVs
Likely not CYP related (p-gp?)
Boosted PI and COBI usually decrease (?) ethinyl estradiol AUC 37-48%
Boosted atazanavir need to use >35mcg EE
All others - use back-up method
NNRTIs: Nevirapine and Efavirenz significantly decrease effectiveness of most OCP - use back-up methods

Rilpivirine and etravirine may be used with OCP safely
Efavirenz decreases levonorgestrel AUC 58% - Plan B effectiveness limited
Raltegravir may be used with OCPs safely
DMPA and LNG-IUS safe with most ARV
Cardiac Medications and ARV
Careful Monitoring Required for:
Warfarin & Rivaroxaban - increased or decreased effects possible with PI/NNRTI/COBI

Antiarrhymics with COBI: Digoxin Cmax increased

Calcium Channel Blockers:
PI/COBI tend to increase effects
NNRTI tend to decrease effects (EFV,NVP especially)

AVOID clopidogrel with etravirine: decreased activation of clopidogrel to active metabolite
AVOID Avanafil with ARV agents (AUC increased 13-fold with ritonavir)
Inhaled/Intranasal Glucocorticoids
Avoid use of fluticasone and budesonide with ritonavir-boosted PI (and COBI?)
350-fold increase fluticasone AUC with ritonavir
Cases of Cushing's Syndrome and Adrenal Insufficiency
Antidepressants
SSRI levels can be increased or decreased with PI/NNRTI/COBI

Start low - Go slow
Efavirenz CNS symptoms can be additive to underlying mental health condition - use with caution

?Which of the preferred ARV Regimens would you recommend?

TB Clinic to provide DOT with Rifampin-based TB therapy

Atazanavir/Ritonavir and Darunavir/Ritonavir not recommended

Raltegravir (BID) and dose increased to 800mg BID with tenofovir/emtricitabine

efavirenz/tenofovir/emtricitabine no dose adjustment necessary - recommended for this patient.
Case 2:
65 yo man successfuly treated HIV for decades (resistance in past) (VL UD, CD4 nadir 75 now 525)
Dyslipidemia: Chol 230, HDL 24, LDL 166, TG 325
Current Meds:
atazanavir 300mg daily
ritonavir 100mg daily
tenofovir/emtricitabine 300/200 daily
aspirin daily
HCTZ/lisinopril 25/20 daily
metformin 1000mg BID
occasional antacids for heart burn
MD wrote new Rx for atorvastatin 10mg daily, insurance company denied as prefer formulary statin: simvastain, lovastatin or pravastatin

?How do you respond to insurance request?

Definate drug-drug interactions:

Atazanavir/tenofovir: Pt appropriately dosed and boosted with Ritonavir

Atazanavir/tenofovir/antacids: Separate 2 hours from admin Calcium Carbonate
NTE 20mg BID famotidine and consider dose increase 400mg atazanavir
Avoid PPI

?How do you responds to insurance request?

Submit Prior Authorization:
Justification - due to significant drug-drug interactions, cannot use simvastatin/lovastatin.

Could switch to pravastatin - given lipids recommend 40mg daily (less potent than atorvastatin)
Case 3:
24yo woman recently diagnosed with HIV (CD4 450 VL 400,000). Was pregnant at time of diagnosis - miscarriage. Also has uncontrolled diabetes (HgA1C 13.5), asthma and depression.
Current Meds:
raltegravir 400mg BID
abacavir/lamivudine 600/300mg daily
metformin 850mg daily
glipizide 10mg daily
Insulin pens daily as directed by BS
Ortho Tri-cyclen
citalopram 40mg daily
Advair 250/50 BID
D
ue to poor adherence to BID HIV regimen, provider changes regimen to darunavir/ritonavir 800/100mg with abacavir/lamivudine

?Do you want to make any other changes to this regimen?

Definate drug-drug interactions:

Darunavir/ritonavir & ethinyl estradiol/norgestimate

Use additional method of birth control (condoms)
Consider switch to DMPA or LMG-IUD

Darunavir/ritonavir and fluticasone/salmeterol

Switch to beclomethasone (Qvar) & albuterol
May need Prior Authorization from Insurance Company to access

Darunavir/ritonavir and citalopram
Monitor effectiveness/toxicities
Avoid sertraline (levels more consistently decreased with darunavir/ritonavir)
Case 4:
Newly diagnosed 52yo man, with underlying seizure disorder - may have been due to alcohol use in past - now sober for 5 years. No seizures of 3 years.

Current Meds:
Phenytoin 300mg at bedtime
Gabapentin 300mg TID
Omeprazole 40mg daily

Pt wants to start HIV therapy - prefers once daily regimen, but does not care how many pills.
?How would you counsel this patient about his HIV Antiretroviral options?

Preferred Regimens:


Avoid due to phenytoin bidirectional interaction
Avoid due to omeprazole use

Efavirenz/tenofovir/emtricitabine
Avoid due to phenytoin bidirectional interaction
Avoid due to pt desire to avoid CNS effects (already having trouble sleeping)

Raltegravir with tenofovir/emtricitabine
Reasonable option (unknown UGAT-1 intxn with phenytoin) - consider raltegravir serum levels
BID dosing not pt preference

Darunavir/ritonavir with tenofovir/emtricitabine
Avoid use of phenytoin due to bidirectional interaction
Consider switch to levetiracetam (or discontinue antisz meds)
Atazanavir/ritonavir with tenofovir/emtricitabine:
Case 5:
28 yo man newly diagnosed with HIV (CD4 680 VL 200,000) and has underlying schizophrenia.
Current Meds:
Aripiprazole 1mg BID
efavirenz/tenofovir/emtricitabine - started 4 weeks ago.

Patient coming in for lab draw, highly anxious - wants to stop HIV medicines because not sleeping and "crawling out of his skin" - unless another one--pill once/day option available. He also plans to ask psychiatrist for increase dose of Abilify at appt next week - still hearing voices.

What suggestions would you suggest to pt and psychiatrist?

One Pill Once a Day options:

Rilpivirine/tenofovir/emtricitabine:
Avoid due to high baseline VL (not recommended with VL >100,000)

Elvitegravir/cobicistat/tenofovir/emtricitabine
Alternative regimen if pt with CrCl >70 ml/min
Additive renal effects cobicistat (asymtomatic) and tenofovir (renal toxic).

Aripiprazole: potent CYP3A4 enzyme induces and inhibitors can affect levels - monitor carefully
Moving from potent inducer to inhibitor - avoid dose increase next week, because EVG/COBI will be offerring increased aripiprazole exposure
MEGA Case
A new patient comes to your pharmacy to fill a monts supply of the following new medications before he runs over to the methadone clinic:
Simvastatin
Diltiazem
Cialis (tadalafil, PRN)
Esomeprazole
St. John's Wort
His HIV meds are:
Maraviroc
Enfuvirtide
didanosine
tenofovir/emtricitanvie
Atazanavir
Ritonavir
Can you find at least 10 interactions?

didanosine-tenofovir: ddI levels increase
atazanavir-ritonavir: therapeutic boosting effect
atazanavir-didanosine: didanosine levels decrease
maraviroc-atazanavir/ritonavir: maraviroc levels increase, dose adjust
simvastatin-atazanavir/ritonavir: avoid use d/t increased simvastatin levels
diltiazem-atazanavir/ritonavir: increased diltiazem levels
methadone- atazanavir/ritonavir: poss decrease methadone levels
esomperazole-atazanavir: need to check doses, timing and evidence of resistance
St. John's Wort - atazanavir/ritonavir: decreased ARV levels avoid use
Tadalafil- atazanavir/ritonavir: increased tadalafil effects
Can you find at least 10 interactions?
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