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Drug Interactions between dexamethasone / ketorolac / moxifloxacin and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

This report displays the potential drug interactions for the following 2 drugs:

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Major

dexAMETHasone moxifloxacin

Applies to: dexamethasone / ketorolac / moxifloxacin and dexamethasone / ketorolac / moxifloxacin

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

References (7)
  1. (2002) "Product Information. Cipro (ciprofloxacin)." Bayer
  2. (2001) "Product Information. Levaquin (levofloxacin)." Ortho McNeil Pharmaceutical
  3. (2001) "Product Information. Avelox (moxifloxacin)." Bayer
  4. Khaliq Y, Zhanel GG (2003) "Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature." Clin Infect Dis, 36, p. 1404-1410
  5. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH (2003) "Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids." Arch Intern Med, 163, p. 1801-7
  6. FDA. U.S. Food and Drug Administration (2008) Information for Healthcare Professionals. Fluoroquinolone Antimicrobial Drugs. FDA Alert [7/8/2008]. http://www.fda.gov/cder/drug/InfoSheets/HCP/fluoroquinolonesHCP.htm
  7. (2017) "Product Information. Baxdela (delafloxacin)." Melinta Therapeutics, Inc.

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Major

ketorolac tenofovir

Applies to: dexamethasone / ketorolac / moxifloxacin and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

GENERALLY AVOID: Coadministration of tenofovir with other nephrotoxic agents may increase the risk of renal impairment due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of tenofovir, which is primarily eliminated by a combination of glomerular filtration and active tubular secretion. The use of tenofovir has been associated with dose-related nephrotoxicity including acute renal failure and Fanconi syndrome characterized by renal tubular injury with severe hypophosphatemia, possibly as a result of mitochondrial toxicity. Cases of acute renal failure after initiation of high-dose or multiple nonsteroidal anti-inflammatory agents have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir therapy. Some patients required hospitalization and renal replacement therapy. Available clinical data seem to suggest a lower risk of nephrotoxicity with tenofovir alafenamide fumarate (TAF) than with tenofovir disoproxil fumarate (TDF), presumably due to lower tenofovir systemic exposure following administration of TAF relative to TDF. Whereas TDF is metabolized in plasma to tenofovir and phosphorylated intracellularly to the active moiety tenofovir diphosphate, TAF is largely metabolized and phosphorylated intracellularly, resulting in substantially higher intracellular concentrations of tenofovir diphosphate and lower plasma levels of tenofovir at the therapeutic dose of 25 mg compared to TDF 300 mg. It has been further reported that tenofovir is actively transported into the proximal renal tubular cell by organic anion transporters (OAT) 1 and 3, but that TAF is not a substrate for these transporters and thus less likely to cause tubular injury. There have been no cases of Fanconi syndrome or proximal renal tubulopathy in clinical trials of various TAF-containing products according to the manufacturers.

MANAGEMENT: The use of tenofovir in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and ganciclovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine) should be avoided if possible. Renal function tests including serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein should be performed prior to and during therapy with tenofovir. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

References (8)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
  2. (2004) "Product Information. Truvada (emtricitabine-tenofovir)." Gilead Sciences
  3. (2015) "Product Information. Genvoya (cobicistat/elvitegravir/emtricitabine/tenofov)." Gilead Sciences
  4. (2016) "Product Information. Odefsey (emtricitabine/rilpivirine/tenofovir)." Gilead Sciences
  5. (2016) "Product Information. Descovy (emtricitabine-tenofovir)." Gilead Sciences
  6. (2017) "Product Information. Vemlidy (tenofovir)." Gilead Sciences
  7. Wang H, Lu X, Yang X, Xu N (2016) "The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy: Meta-analysis." Medicine (Baltimore), 95, e5146
  8. Sax PE, Zolopa A, Brar A, et al. (2014) "Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study." J Acquir Immune Defic Syndr, 67, p. 52-8

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Major

moxifloxacin lopinavir

Applies to: dexamethasone / ketorolac / moxifloxacin and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

GENERALLY AVOID: Certain quinolones, including gatifloxacin and moxifloxacin, may cause dose-related prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. During postmarketing surveillance, rare cases of torsade de pointes have been reported in patients taking gatifloxacin. These cases primarily involved patients with underlying medical conditions for which they were receiving concomitant medications known to prolong the QTc interval. Rare cases of tachycardia have been reported with moxifloxacin. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of gatifloxacin or moxifloxacin with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

References (26)
  1. (2001) "Product Information. Avelox (moxifloxacin)." Bayer
  2. (2001) "Product Information. Tequin (gatifloxacin)." Bristol-Myers Squibb
  3. Siepmann M, Kirch W (2001) "Drug points - Tachycardia associated with moxifloxacin." Br Med J, 322, p. 23
  4. Owens RC (2001) "Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes." Pharmacotherapy, 21, p. 301-19
  5. Iannini PB, Circiumaru I (2001) "Gatifloxacin-induced QTc prolongation and ventricular tachycardia." Pharmacotherapy, 21, p. 361-2
  6. Demolis JL, Kubitza D, Tenneze L, Funck-Bretano C (2000) "Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects." Clin Pharmacol Ther, 68, p. 658-66
  7. Iannini PB, Doddamani S, Byazrova E, Curciumaru I, Kramer H (2001) "Risk of torsades de pointes with non-cardiac drugs." BMJ, 322, p. 46-7
  8. Ball P (2000) "Quinolone-induced QT interval prolongation: a not-so-unexpected class effect." J Antimicrob Chemother, 45, p. 557-9
  9. Kang J, Wang L, Chen XL, Triggle DJ, Rampe D (2001) "Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG." Mol Pharmacol, 59, p. 122-6
  10. White CM, Grant EM, Quintiliani R (2001) "Moxifloxacin does increase the corrected QT interval." Clin Infect Dis, 33, p. 1441-2
  11. Frothingham R (2001) "Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin." Pharmacotherapy, 21, p. 1468-72
  12. Bertino JS Jr, Owens RC Jr, Carnes TD, Iannini PB (2002) "Gatifloxacin-associated corrected QT interval prolongation, torsades de pointes, and ventricular fibrillation in patients with known risk factors." Clin Infect Dis, 34, p. 861-3
  13. Oliphant CM, Green GM (2002) "Quinolones: a comprehensive review." Am Fam Physician, 65, p. 455-64
  14. Owens RC Jr, Ambrose PG (2002) "Torsades de pointes associated with fluoroquinolones." Pharmacotherapy, 22, 663-8; discussion 668-72
  15. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R (2003) "Effects of three fluoroquinolones on QT interval in healthy adults after single doses." Clin Pharmacol Ther, 73, p. 292-303
  16. Ansari SR, Chopra N (2004) "Gatifloxacin and Prolonged QT Interval." Am J Med Sci, 327, p. 55-6
  17. Iannini PB (2002) "Cardiotoxicity of macrolides, ketolides and fluoroquinolones that prolong the QTc interval." Expert Opin Drug Saf, 1, p. 121-8
  18. Owens RC (2004) "QT Prolongation with Antimicrobial Agents : Understanding the Significance." Drugs, 64, p. 1091-124
  19. Katritsis D, Camm AJ (2003) "Quinolones: cardioprotective or cardiotoxic." Pacing Clin Electrophysiol, 26, p. 2317-20
  20. Stahlmann R (2002) "Clinical toxicological aspects of fluoroquinolones." Toxicol Lett, 127, p. 269-77
  21. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  22. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  23. Dale KM, Lertsburapa K, Kluger J, White CM (2007) "Moxifloxacin and torsade de pointes." Ann Pharmacother, 41, p. 336-40
  24. Falagas ME, Rafailidis PI, Rosmarakis ES (2007) "Arrhythmias associated with fluoroquinolone therapy." Int J Antimicrob Agents, 29, p. 374-9
  25. Tsikouris JP, Peeters MJ, Cox CD, Meyerrose GE, Seifert CF (2006) "Effects of three fluoroquinolones on QT analysis after standard treatment courses." Ann Noninvasive Electrocardiol, 11, p. 52-6
  26. Cerner Multum, Inc. "Australian Product Information."

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Moderate

dexAMETHasone ketorolac

Applies to: dexamethasone / ketorolac / moxifloxacin and dexamethasone / ketorolac / moxifloxacin

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

References (11)
  1. Stewart JT, Pennington CR, Pringle R (1985) "Anti-inflammatory drugs and bowel perforations and haemorrhage." Br Med J, 290, p. 787-8
  2. Thomas TP (1984) "The complications of systemic corticosteroid therapy in the elderly." Gerontology, 30, p. 60-5
  3. Messer J, Reitman D, Sacks HS, et al. (1983) "Association of adrenocorticosteroid therapy and peptic-ulcer disease." N Engl J Med, 309, p. 21-4
  4. ReMine SG, McIlrath DC (1980) "Bowel perforation in steroid-treated patients." Ann Surg, 192, p. 581-6
  5. Levy M, Miller DR, Kaufman DW, Siskind V, Schwingl P, Rosenberg L, Strom B, Shapiro S (1988) "Major upper gastrointestinal tract bleeding. Relation to the use of aspirin and other nonnarcotic analgesics." Arch Intern Med, 148, p. 281-5
  6. Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm BE, Alfredsson L, Koff RS, Shapiro S (1993) "Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding." Clin Pharmacol Ther, 53, p. 485-94
  7. Wilcox CM, Shalek KA, Cotsonis G (1994) "Striking prevalence of over-the-counter nonsteroidal anti- inflammatory drug use in patients with upper gastrointestinal hemorrhage." Arch Intern Med, 154, p. 42-6
  8. Cantu TG, Lipani JA (1995) "Gastrointestinal ulceration with NSAIDs." Am J Med, 99, p. 440-1
  9. Sacanella E, Munoz F, Cardellach F, Estruch R, Miro O, Urbanomarquez A (1996) "Massive haemorrhage due to colitis secondary to nonsteroidal anti-inflammatory drugs." Postgrad Med J, 72, p. 57-8
  10. Buchman AL, Schwartz MR (1996) "Colonic ulceration associated with the systemic use of nonsteroidal antiinflammatory medication." J Clin Gastroenterol, 22, p. 224-6
  11. Piper JM, Ray WA, Daugherty JR, Griffin MR (1991) "Corticosteroid use and peptic ulcer disease: role of nonsteroidal ani-inflammatory drugs." Ann Intern Med, 114, p. 735-40

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Moderate

dexAMETHasone ritonavir

Applies to: dexamethasone / ketorolac / moxifloxacin and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

GENERALLY AVOID: Coadministration with protease inhibitors may increase the plasma concentration and pharmacologic effects of dexamethasone. The proposed mechanism is protease inhibitor-mediated inhibition of CYP450 3A4, the isoenzyme involved in the metabolic clearance of dexamethasone. Ritonavir has been reported to increase dexamethasone systemic exposure (AUC) by more than threefold. In one case report, an HIV patient who had been receiving long-term dexamethasone therapy for thrombotic thrombocytopenia purpura developed spinal epidural lipomatosis four months following the initiation of ritonavir. Although the patient was already cushingoid as a result of chronic dexamethasone administration, he did not have symptoms of myelopathy until after ritonavir was added. The effect of dexamethasone on the clearance of protease inhibitors has not been established. Theoretically, plasma levels of protease inhibitors may decrease due to dexamethasone induction of their metabolism by CYP450 3A4. This may lead to a loss of therapeutic effect and development of resistance to protease inhibitor-containing antiretroviral regimens; however, data are not available. These interactions may also be seen with cobicistat, a potent CYP450 3A4 inhibitor that solely acts as a pharmacokinetic booster in antiretroviral treatment regimen; however, data are not available.

MONITOR: Corticosteroids such as dexamethasone may cause hypokalemia and potentiate the risk of QT and/or PR interval prolongation associated with the use of certain protease inhibitors such as atazanavir, lopinavir-ritonavir, and saquinavir-ritonavir. The risk of torsade de pointes arrhythmia, bradycardia, and heart block may be increased.

MANAGEMENT: Caution is advised if dexamethasone must be used concomitantly with protease inhibitors or cobicistat. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. Adrenal function should be monitored regularly during chronic use of these agents, and dexamethasone dosage adjusted as necessary. Patients should be monitored for symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, and irregular menstruations), immunosuppression, and osteoporosis. In addition, it may be appropriate to monitor patients for potentially reduced antiretroviral response following initiation or any dosage increase of dexamethasone. Serum potassium and ECG monitoring should also be considered during coadministration of dexamethasone with certain protease inhibitors in accordance with the product labeling.

References (3)
  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  3. Cerner Multum, Inc. "Australian Product Information."

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Moderate

dexAMETHasone lopinavir

Applies to: dexamethasone / ketorolac / moxifloxacin and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

MONITOR: Coadministration of lopinavir-ritonavir with inducers of CYP450 3A4 may decrease the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. Clinical studies have shown that potent CYP450 3A4 inducers such as rifampin and phenytoin can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the inhibiting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 20 days) with rifampin (600 mg once daily for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively. In another study of 12 healthy volunteers, coadministration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) and phenytoin (300 mg once daily on days 11 through 22) resulted in decreases in Cmax, AUC and Cmin of lopinavir by 24%, 33% and 46%, respectively. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant. The extent to which other, less potent inducers of CYP450 3A4 may interact with lopinavir-ritonavir is unknown. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with CYP450 3A4 inducers. Close clinical and laboratory monitoring of antiretroviral response is recommended. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.

References (5)
  1. Brooks J, Daily J, Schwamm L (1997) "Protease inhibitors and anticonvulsants." AIDS Clin Care, 9, 87,90
  2. Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, DelGiudice P, Montagne N, Schapiro JM, Dellamonica P (2000) "Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study." Aids, 14, p. 1333-9
  3. (2001) "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical
  4. Liedtke MD, Lockhart SM, Rathbun RC (2004) "Anticonvulsant and antiretroviral interactions." Ann Pharmacother, 38, p. 482-9
  5. Lim ML, Min SS, Eron JJ, et al. (2004) "Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction." J Acquir Immune Defic Syndr, 36, p. 1034-40

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Moderate

ketorolac moxifloxacin

Applies to: dexamethasone / ketorolac / moxifloxacin and dexamethasone / ketorolac / moxifloxacin

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.

References (14)
  1. Ball P (1986) "Ciprofloxacin: an overview of adverse experiences." J Antimicrob Chemother, 18, p. 187-93
  2. Hooper DC, Wolfson JS (1985) "The fluoroquinolones: pharmacology, clinical uses, and toxicities in humans." Antimicrob Agents Chemother, 28, p. 716-21
  3. (2002) "Product Information. Cipro (ciprofloxacin)." Bayer
  4. (2002) "Product Information. Penetrex (enoxacin)." Rhone Poulenc Rorer
  5. (2001) "Product Information. Floxin (ofloxacin)." Ortho McNeil Pharmaceutical
  6. Domagala JM (1994) "Structure-activity and structure-side-effect relationships for the quinolone antibacterials." J Antimicrob Chemother, 33, p. 685-706
  7. (2001) "Product Information. Levaquin (levofloxacin)." Ortho McNeil Pharmaceutical
  8. (2001) "Product Information. Raxar (grepafloxacin)." Glaxo Wellcome
  9. Davey PG (1988) "Overview of drug interactions with the quinolones." J Antimicrob Chemother, 22(suppl c), p. 97-107
  10. Ball P, Tillotson G (1996) "Tolerability of fluoroquinolone antibiotics: past, present and future." Drug Saf, 13, p. 343-8
  11. (2001) "Product Information. Avelox (moxifloxacin)." Bayer
  12. (2001) "Product Information. Tequin (gatifloxacin)." Bristol-Myers Squibb
  13. (2003) "Product Information. Factive (gemifloxacin)." *GeneSoft Inc
  14. Segev S. Rehavi M, Rubinstein E (1988) "Quinolones, theophylline, and diclofenac interactions with the gamma-aminobutyric acid receptor." Antimicrob Agents Chemother, 32, p. 1624-6

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Moderate

ritonavir tenofovir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

References (8)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
  2. Verhelst D, Monge M, Meynard JL, et al. (2002) "Fanconi syndrome and renal failure induced by tenofovir: A first case report." Am J Kidney Dis, 40, p. 1331-3
  3. Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D (2003) "Renal lesions in HIV-1-positive patient treated with tenofovir." AIDS, 17, p. 935-7
  4. Karras A, Lafaurie M, Furco A, et al. (2003) "Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus." Clin Infect Dis, 36, p. 1070-3
  5. Kearney BP, Mittan A, Sayre J, et al. (2003) Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. http://www.icaac.org/ICAAC.asp
  6. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. (2003) "Tenofovir-related fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-Didanosine." Clin Infect Dis, 37, E174-6
  7. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G (2006) "Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions." Clin Infect Dis, 42, p. 283-90
  8. Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2

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Moderate

lopinavir tenofovir

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

References (8)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences
  2. Verhelst D, Monge M, Meynard JL, et al. (2002) "Fanconi syndrome and renal failure induced by tenofovir: A first case report." Am J Kidney Dis, 40, p. 1331-3
  3. Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D (2003) "Renal lesions in HIV-1-positive patient treated with tenofovir." AIDS, 17, p. 935-7
  4. Karras A, Lafaurie M, Furco A, et al. (2003) "Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, fanconi syndrome, and nephrogenic diabetes insipidus." Clin Infect Dis, 36, p. 1070-3
  5. Kearney BP, Mittan A, Sayre J, et al. (2003) Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinavir/ritonavir. http://www.icaac.org/ICAAC.asp
  6. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. (2003) "Tenofovir-related fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-Didanosine." Clin Infect Dis, 37, E174-6
  7. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G (2006) "Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions." Clin Infect Dis, 42, p. 283-90
  8. Kapadia J, Shah S, Desai C, et al. (2013) "Tenofovir induced Fanconi syndrome: a possible pharmacokinetic interaction." Indian J Pharmacol, 45, p. 191-2

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Drug and food interactions

Moderate

ritonavir food

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References (1)
  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical

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Moderate

lopinavir food

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

ADJUST DOSING INTERVAL: Food significantly increases the bioavailability of lopinavir from the oral solution formulation of lopinavir-ritonavir. Relative to fasting, administration of lopinavir-ritonavir oral solution with a moderate-fat meal (500 to 682 Kcal; 23% to 25% calories from fat) increased lopinavir peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 80%, respectively, whereas administration with a high-fat meal (872 Kcal; 56% from fat) increased lopinavir Cmax and AUC by 56% and 130%, respectively. No clinically significant changes in Cmax and AUC were observed following administration of lopinavir-ritonavir tablets under fed conditions versus fasted conditions. Relative to fasting, administration of a single 400 mg-100 mg dose (two 200 mg-50 mg tablets) with a moderate-fat meal (558 Kcal; 24.1% calories from fat) increased lopinavir Cmax and AUC by 17.6% and 26.9%, respectively, while administration with a high-fat meal (998 Kcal; 51.3% from fat) increased lopinavir AUC by 18.9% but not Cmax. Relative to fasting, ritonavir Cmax and AUC also increased by 4.9% and 14.9%, respectively, with the moderate-fat meal and 10.3% and 23.9%, respectively, with the high-fat meal.

MANAGEMENT: Lopinavir-ritonavir oral solution should be taken with meals to enhance bioavailability and minimize pharmacokinetic variability. Lopinavir-ritonavir tablets may be taken without regard to meals.

References (1)
  1. (2001) "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical

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Moderate

ketorolac food

Applies to: dexamethasone / ketorolac / moxifloxacin

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

References (1)
  1. (2002) "Product Information. Motrin (ibuprofen)." Pharmacia and Upjohn

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Minor

tenofovir food

Applies to: emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.

References (1)
  1. (2001) "Product Information. Viread (tenofovir)." Gilead Sciences

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.