- Use of low molecular weight or unfractionated heparin recommended depending on the situation
- Antivitamin K and DOACs are not recommended 
- Effects of some drugs may be reduced in effect by combination with enzyme inhibitors like lopinavir

Anticoagulants and antiplatelet drugs

- Statin toxicity can be increased by additive effects in combination with lopinavir
- Monitoring is necessary and statin dosage may have to be reduced
- Pravastatin is least prone to interactions

Lipid lowering drugs

- Combining eplerenone with lopinavir/ritonavir (lopinavir/r) increases the plasma exposure of eplerenone.
- Replacing eplerenone with spironolactone is worth consideration to mitigate this drug-drug interaction.

Drugs in heart failure

Anti-hypertensive drugs exhibit varying pharmacokinetic interactions with COVID-19 treatments. While sartans and diuretics are not prone to significant interactions, combining calcium channel blockers (CCBs) or beta blockers with lopinavir/ritonavir (lopinavir/r) can increase the plasma exposure of the anti-hypertensives. Furthermore, hydroxychloroquine can also increase the exposure of beta blockers. The concurrent use of the beta blocker metoprolol with lopinavir/r is contraindicated.

Anti-hypertensive Interactions with Lopinavir/ritonavir and Hydroxychloroquine

- Ivabradine is extensively metabolized by CYP3A4 and has significant pharmacokinetic interactions with lopinavir/ritonavir, making concurrent use contraindicated.
- Combining these drugs can lead to significantly increased plasma concentrations of ivabradine, potentially causing severe bradycardia.

Interaction of Ivabradine with Lopinavir/ritonavir

Lopinavir/ritonavir can increase exposure to the class I anti-arrhythmic drugs quinidine and propafenone, potentially causing cardiac disorders; ECG monitoring is required. Combining lopinavir/ritonavir with class III anti-arrhythmic drugs such as amiodarone is contraindicated because of the increased risk of torsades de pointes.

Interactions of Anti-arrhythmic Drugs with Lopinavir/Ritonavir

Lopinavir/ritonavir can cause hyperglycemia and increase the exposure and concentration of gliptins, while ritonavir can reduce sulfonylurea exposure. Hydroxychloroquine can worsen hypoglycemia. Oral antidiabetic treatment in patients with COVID-19 receiving these drugs therefore requires case-by-case assessment.

Oral Antidiabetic Drug Interactions with Lopinavir/Ritonavir and Hydroxychloroquine

- Anticoagulants and antiplatelet drugs
- Lipid lowering drugs
- Anti-hypertensives
- Drugs in heart failure
- Drugs in angina pectoris
- Anti-arrhythmic drugs
- Oral anti-diabetics

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- antipyretics and analgesics
- drugs in cardiovascular diseases
- drugs in infectious diseases
- anti cancer drugs
- drugs in transplantation and autoimmune diseases
- drugs in neuropsychiatric diseases
- drugs in respiratory diseases

Assessment and Management of the Risk of Drug-Drug Interactions with Other Widely Used Drugs

- Anticancer treatment must be suspended for patients with COVID-19 in ICU
- Highly cytotoxic chemotherapy should be avoided in COVID-19 infection
- Possible additive cardiotoxicity between protein kinase inhibitors and hydroxychloroquine, azithromycin or lopinavir
- Many anticancer drugs can inhibit or induce CYPs which can change the bioavailability or elimination of lopinavir/r, hydroxychloroquine, favipiravir, or remdesivir

Anti-Cancer drugs: cytotoxic, targeted therapy

- When co-administered with hydroxychloroquine, calcineurin inhibitors and m-TOR inhibitors can cause QT prolongation
- Increased exposure of hydroxychloroquine with ciclosporin
- Must reduce dose of lopinavir/r with immunosuppressants due to its strong inhibition of CYP3A, OATP1B1, and OATP1B3 to prevent nephrotoxicity and neurotoxicity  
- Therapeutic drug monitoring needed in combination with lopinavir/r
- Baricitinib may increase immunosuppression in combination with immunosuppressants 
- Combination of anakinra and methotrexate or TNF-alpha not recommended 

Drugs in organ transplantation and autoimmune disease

Antidepressants:
- Do not combine citalopram or escitalopram with hydroxychloroquine due to risk of torsades de pointes by increasing the QT interval

Anxiolytics:
- Use of hydroxyzine with hydroxychloroquine is contraindicated due to the torsadogenic risk

Antipsychotics:
- Increased torsadogenic potential of most neuroleptics with hydroxychloroquine but combination not contraindicated

Addiction medication:
- Methadone not recommended with hydroxychloroquine due to dose dependent cardiotoxicity like torsades de pointes

Anti migraines:
- Use of azithromycin is contraindicated with ergot derivatives, ergotamine and dihydroergotamine

Antiepileptics: 
- Risk of interactions from old anticonvulsants including but not limited to phenytoin and phenobarbital due to enzyme inducing effects

Drugs in neuropsychiatric diseases

Anti-asthmatics:
- Ritonavir was show to increase the plasma exposure of fluticasone by more than 100 times and thus this combination should be avoided
- Strong CYP3A4 inhibitors like lopinavir/r can increase exposure of budesonide and salmeterol
- Increased salmeterol exposure can lead to QT prolongation and palpitations
- Theophylline exposure may be altered by lopinavir/r so both must be used with caution

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