Darunavir / cobicistat

Digoxin

Monitor more closely.

No pharmaceutical opinion available for this interaction.

Mechanism

Darunavir / cobicistat can decrease the P-gp and increase the plasma concentration of Digoxin.

Darunavir / cobicistat

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Digoxin

Pharmacodynamic effects

Possible increase of adverse effects, especially if the patient has kidney failure.

Recommendations

Use with caution, monitor drug concentrations.

Start with a small dose or reduce the dose if already used.

Monitor for adverse effects and adjust the dosage.

In patients already being treated with this combination and tolerating it, if deemed appropriate, keep actual treatment and exercise close monitoring of adverse effects.

Alternative solution(s)

Monitor

Adverse effects of digoxin: Gastrointestinal effects (abdominal discomfort, nausea/vomiting, diarrhea, anorexia, dyspepsia), central nervous system effects, vision disorders, fatigue, headache, bradycardia and rhythm disorders.

EKG

Tests

Digoxinemia

Pharmacokinetic parameters

Comment

Ref #758: One case report of digoxin-related toxicity 3 days after the addition of ritonavir 200 mg BID to a regimen that included digoxin 0.25 mg, lamivudine, indinavir, staduvine, coumadin and pentamidine.

Ref #1943 : Study in healthy subjects who received a single dose of digoxin 0.4 mg PO and ritonavir 200 mg BID for 14 days given before and after digoxin. Authors conclude that digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration.

Ref #1941 : Study in 12 healthy subjects receiving ritonavir 300 mg BID for 11 days (ritonavir at steady state) and IV digoxin for 3 days. Ritonavir decreased renal and non-renal clearance of digoxin by 48% and 35%, respectively. There is also an increase in terminal T1/2 of 156% (P <0.01) and in digoxin AUC of 86%.

Ref #2075 : One study showed a 49% increase in AUC of digoxin when administered with saquinavir / ritonavir. Furthermore, the renal clearance has increased from 97.3 to 111 ml/min, while the half-life increased from 37.0 to 45.3 hours.

Ref #2107 : Coadministration of digoxin (0.4 mg) and darunavir/ritonavir (600/100 mg twice daily) was studied in 8 healthy subjects. Digoxin Cmax increased by 15% and AUC increased by 36%.

Ref # 3482: Case report of digoxin toxicity in a 51-year-old HIV+ man with digoxin 0.25 mg who experienced digoxin toxicity symptoms (nausea, vomiting and weight loss) and atrial flutter after starting darunavir (800 mg), ritonavir (100 mg), dolutegravir (50 mg) and rilpivirine (25 mg). After a change in antiretroviral therapy for efavirenz, abacavir and dolutegravir, the symptoms disappeared and the ECG returned to normal.

The European guidelines recommend to reduce digoxin dose by half when a PI is started. While for patients already on a PI-based therapy, digoxin should be started at the lowest dose.

Ritonavir Canadian Product Monograph stipulates that care must be taken when administering ritonavir in combination with digoxin and perform adequate monitoring of digoxin plasma concentrations.

Increased PR or QTc interval prolongation on ECG, atrioventricular or bundle branch blocks, and rare cases of torsades de pointes with viral protease inhibitors have been observed in cohort studies and case reports. However, the benefits of using protease inhibitors exceed the risks associated with this effect.

To avoid the risk of QT interval prolongation, it is recommended that no antiarrhythmic be coadministered with drugs that prolong the QT interval (see www.qtdrugs.org). This is especially important for patients with high baseline QTc values or risk factors for dysrhythmia (patients with a conduction disorder; ischemic heart disease; cardiomyopathy; hypocalcemia, hypokalemia or refractory hypomagnesemia; bradycardia; an initial QT interval > 500 ms). The risk is even higher since PIs can decrease the metabolism of most antiarrhythmics.

Reference
  • 758
    Phillips EJ, Rachlis AR. Digoxin toxicity and ritonavir - a drug interaction mediated through P-glycoprotein? 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Noordwijk, the Netherlands, April 2-4, 2001. Abstract 1.9
  • 1943
    Penzak SR, Shen JM, Alfaro RM, et al. Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes. Ther Drug Monitor 2004; 26(3):322-330.
  • 1941
    Ding R, Tayrouz Y, Riedel KD, et al. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 2004; 76(1):73-84.
  • 2075
    Schmitt C, Kaeser B, Riek M, Bech N, Kreuzer C. Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe. Int J Clin Pharmacol Ther. 2010 Mar; 48 (3): 192-199.
  • 2107
    Darunavir (Prezista), Janssen, Ontario, Canada, 23 mai 2018.
  • 3482
    Yoganathan K, Roberts B, Heatley M. Life-threatening digoxin toxicity due to drug-drug interactions in an HIV-positive man.. Int J STD AIDS, 2017, 18(3): 297-301.
  • 3071
    Darunavir/cobicistat (Prezcobix), Janssen, Ontario, Canada, 7 avril 2017.
  • 2707
    Digoxin, Sandoz Inc., Québec, Canada, 21 octobre 2016.
  • 1942
    Englund G, Hallberg P, Artursson P, et al. Association between the number of co-administered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring. BMC Med 2004;2(8):1-7.
  • 3437
    Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza), Janssen Inc, Ontario, Canada, 3 octobre 2018.
  • 3149
    Kirby BJ, Collier AC, Kharasch ED, et al. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab Dispos, 2012, 40(3): 610-6.