Clinically Relevant Drug-Drug Interactions in Primary Care

Mary Carpenter, PharmD; Holly Berry, PharmD; Allen L. Pelletier, MD

Am Fam Physician. 2019;99(9):558-564.

Clonidine and Beta Blockers

Several reports describe an increased hypertensive response to the withdrawal of clonidine when a beta blocker is being used.^[39] In the presence of a beta2-receptor blockade, the vasoconstrictor properties of the catecholamines are unopposed, resulting in the exaggerated hypertensive response within 24 to 72 hours after discontinuation of clonidine.^[39] Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension. Recommendations call for decreasing the dosage of clonidine over several days before discontinuation.^[40]

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Table 1. Warfarin and Antimicrobial Interactions and Dosing Recommendations
Interacting drug	Effect on international normalized ratio	Warfarin (Coumadin) adjustment recommendation
Trimethoprim/sulfamethoxazole¹¹	Increase	Reduce dosage by 25% to 40%
Metronidazole (Flagyl)¹⁰	Increase	Reduce dosage by 25% to 40%
Azole antifungals¹¹	Increase	Reduce dosage by 25% to 30%
Rifampin¹²	Decrease	Increase dosage by 25% to 50%

Information from references 9 through 12.

Table 2. Dosing Adjustment for Selected Direct Oral Anticoagulant Interactions
Rivaroxaban (Xarelto)²⁶	Apixaban (Eliquis)²⁷	Dabigatran (Pradaxa)²⁸
Avoid use in combination with drugs that are both strong CYP3A4 inhibitors and P-gp inhibitors (e.g., ketoconazole, ritonavir [Norvir])	If prescribing 5 mg or 10 mg twice daily, reduce apixaban dosage by 50% with strong CYP3A4 inhibitor (e.g., ketoconazole)	Treatment for thromboembolism; avoid use with any P-gp inhibitor (e.g., amiodarone) if CrCl < 50 mL per minute per 1.73 m² (0.83 mL per second per m²)
	If prescribing 2.5 mg twice daily, avoid use of apixaban with strong CYP3A4 inhibitor	Treatment for atrial fibrillation; avoid use with any P-gp inhibitor if CrCl < 15 mL per minute per 1.73 m² (0.25 mL per second per m²)

CrCL = creatinine clearance; CYP = cytochrome P450; P-gp = P-glycoprotein.
Information from references 26 through 29.

Table 3. Recommendations for Statin and Calcium Channel Blocker Usage
Simvastatin (Zocor)³⁷
Calcium channel blocker	Management strategy
Amlodipine (Norvasc)	Maximum simvastatin: 20 mg per day
Diltiazem	Maximum simvastatin: 10 mg per day
Diltiazem	Maximum diltiazem: 240 mg per day
Verapamil	Maximum simvastatin: 10 mg per day
Atorvastatin (Lipitor)³⁶
Calcium channel blocker	Management strategy
Diltiazem	Monitor closely for signs or symptoms of muscle toxicity
Verapamil	Monitor closely for signs or symptoms of muscle toxicity

Information from references 36 and 37.

Table 4. Common Over-the-Counter Products That Contain Chelating Cations
Cations	Product names
Aluminum	AlternaGel, Alu-Cap, Amphojel, Basaljel
Aluminum/magnesium combos	Gaviscon, Gelusil, Maalox, Mag-Al, Mylanta
Calcium	Caltrate, Citracal, Os-Cal, PhosLo, Tums
Iron	Feosol, Fergon, Fer-In-Sol, Niferex, Nu-Iron, Slow Fe
Magnesium	Citrate of Magnesium, Mag-Ox 400, Milk of Magnesia, Slow-Mag, Uro-Mag

Information from reference 40.

Table 5. Risk Factors for Torsades de Pointes
Age > 65 years	Hypokalemia
Bradycardia	Hypomagnesemia
Female sex	Underlying heart disease
Higher doses of two or more QT-prolonging drugs

Information from reference 47.

Table 6. Drugs Associated with Moderate and High QTc Prolongation
Drug category	Drug class/name*
Analgesics⁴⁸	Methadone^48–50
Antiarrhythmics⁴⁸	Amiodarone, dofetilide (Tikosyn), dronedarone (Multaq), flecainide (Tambocor), procainamide, quinidine, sotalol (Betapace)
Antidepressants⁴⁹	Citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), tetracycline antidepressants
Antiemetics⁴⁹	Chlorpromazine, ondansetron (Zofran)
Antimicrobials⁵¹	Antimalarials, antiretrovirals, fluoroquinolones, macrolides
Psychotropics⁴⁹	Haloperidol, paliperidone (Invega), quetiapine (Seroquel), ziprasidone (Geodon)
Serotonin agonists⁴⁹	Sumatriptan (Imitrex), zolmitriptan (Zomig)

*—High-risk drugs listed in bold.
Information from references 48 through 51.

Table 7. Drugs with Increased Risk of Central Nervous System Depression
Antipsychotics⁵³	Hypnotics (eszopiclone [Lunesta], zaleplon [Sonata], zolpidem [Ambien])
Barbiturates	Muscle relaxants
Benzodiazepines⁵²	Opioid analgesics⁵⁰

Information from references 50, 52, and 53.

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Sort: Key Recommendations for Practice

Clinical recommendation	Evidence rating	References
Software programs that identify potentially serious drug interactions may reduce risk of harm.	C	2
Pharmacist-directed anticoagulation clinics can identify drug interactions with warfarin (Coumadin) and improve patient outcomes.	B	3, 5
Medication reconciliation and review by a pharmacist as part of a transition of care process can identify potential drug interactions and may improve patient outcomes.	B	4
An empiric warfarin dosage reduction of 30% to 50% upon initiation of amiodarone therapy is recommended.	C	14, 15
Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension.	C	39, 40
If the combination is necessary, the spironolactone dosage should be limited to 25 mg per day when coadministered with potassium supplements.	C	44–46

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Best Practices in Geriatric Medicine

Recommendations from the Choosing Wisely Campaign
Recommendation	Sponsoring organization
Prescribe a medication only after conducting a drug regimen review.	American Geriatrics Society
Do not prescribe medications for patients receiving five or more medications, or continue medications indefinitely, without a comprehensive review of their existing medications, including over-the-counter medications and dietary supplements, to determine whether any of the medications or supplements should or can be discontinued.	American Society of Health-System Pharmacists

Source: For more information on the Choosing Wisely Campaign, see https://www.choosingwisely.org. For supporting citations and to search Choosing Wisely recommendations relevant to primary care, see https://www.aafp.org/afp/recommendations/search.htm.

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Clinically Relevant Drug-Drug Interactions in Primary Care

Clonidine and Beta Blockers

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