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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
Didanosine significant interactions: PK and increased toxicity - AVOID USE!
Searching for Interactions
Framework for Evaluating Drug Interactions
1. OBTAIN complete medication history
2. SEARCH for definate vs probable vs theoretical interactions
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
Elimination (Renal)
Additive Toxicities
NNRTI CYP3A4 inducers & substrates
PI CYP3A4 inhibitors and substrates
Nevirapine>Efavirenz>Rilpivirine for enzyme induction
COBI/PI: No clear data
Statins and ARV Agents
Antiepileptic Drugs and ARV Agents
Methadone and ARV Agents
Likely not CYP related
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:
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
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
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

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:

Avoid due to high baseline VL (not recommended with VL >100,000)

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
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:
Cialis (tadalafil, PRN)
St. John's Wort
His HIV meds are:
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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