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Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and Hismanal

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

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Interactions between your drugs

Major

astemizole ritonavir

Applies to: Hismanal (astemizole) and AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

CONTRAINDICATED: Coadministration with protease inhibitors (PIs), particularly ritonavir, may significantly increase the plasma concentrations of astemizole and terfenadine. The mechanism is PI inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of both astemizole and terfenadine. Although the interaction has not been specifically studied with any of the available PIs, high plasma levels of astemizole and terfenadine (e.g., due to overdose or interaction with other potent 3A4 inhibitors such as macrolide antibiotics and azole antifungal agents) have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of astemizole and terfenadine, use of these agents in patients treated with protease inhibitors is considered contraindicated. Loratadine, cetirizine, or fexofenadine may be safer alternatives during therapy with PIs.

References

  1. Eller MG, Okerholm RA "Pharmacokinetic interaction between terfenadine and ketoconazole." Clin Pharmacol Ther 49 (1991): 130
  2. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr "Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin." Clin Pharmacol Ther 52 (1992): 231-8
  3. Zimmermann M, Duruz H, Guinand O, et al. "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J 13 (1992): 1002-3
  4. Mathews DR, McNutt B, Okerholm R, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 266 (1991): 2375-6
  5. Honig PK, Wortham DC, Zamani K, et al. "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA 269 (1993): 1513-8
  6. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P "Torsades de pointes after terfenadine-itraconazole interaction." BMJ 306 (1993): 186
  7. Craft TM "Torsade de pointes after astemizole overdose." Br Med J 292 (1986): 660
  8. Snook J, Boothman-Burrell D, Watkins J, Colin-Jones D "Torsade de pointes ventricular tachycardia associated with astemizole overdose." Br J Clin Pract 42 (1988): 257-9
  9. Saviuc P, Danel V, Dixmerias F "Prolonged QT interval and torsade de pointes following astemizole overdose." J Toxicol Clin Toxicol 31 (1993): 121-5
  10. Hasan RA, Zureikat GY, Nolan BM "Torsade de pointes associated with astemizole overdose treated with magnesium sulfate." Pediatr Emerg Care 9 (1993): 23-5
  11. Crane JK, Shih HT "Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine." Am J Med 95 (1993): 445-6
  12. Biglin KE, Faraon MS, Constance TD, Lieh-Lai M "Drug-induced torsades de pointes: a possible interaction of terfenadine and erythromycin." Ann Pharmacother 28 (1994): 282
  13. Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR "Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics." J Clin Pharmacol 33 (1993): 1201-6
  14. Rao KA, Adlakha A, Vermaansil B, Meloy TD, Stanton MS "Torsades de pointes ventricular tachycardia associated with overdose of astemizole." Mayo Clin Proc 69 (1994): 589-93
  15. Kivisto KT, Neuvonen PJ, Klotz U "Inhibition of terfenadine metabolism - pharmacokinetic and pharmacodynamic consequences." Clin Pharmacokinet 27 (1994): 1-5
  16. Smith SJ "Cardiovascular toxicity of antihistamines." Otolaryngol Head Neck Surg 111 Suppl (1994): 348-54
  17. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP "Torsades-de-pointes induced by erythromycin and terfenadine." Am J Emerg Med 12 (1994): 636-8
  18. "Product Information. Invirase (saquinavir)." Roche Laboratories PROD (2001):
  19. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
  20. "Product Information. Crixivan (indinavir)." Merck & Co., Inc PROD (2001):
  21. Ng PW, Chan WK, Chan TYK "Torsade de pointes during the concomitant use of terfenadine and cimetidine." Aust N Z J Med 26 (1996): 120-1
  22. Heidemann SM, Sarnaik AP "Arrhythmias after astemizole overdose." Pediatr Emerg Care 12 (1996): 102-4
  23. Woosley RL "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol 36 (1996): 233-52
  24. Hey JA, Delprado M, Egan RW, Kreutner W "Terfenadine, astemizole, and ebastine produce QTc interval prolongation in an experimental model predictive of adverse clinical ECG effects." Ann Allergy Asthma Immunol 76 (1996): 476
  25. Vorperian VR, Zhou ZF, Mohammad S, Hoon TJ, Studenik C, January CT "Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole." J Am Coll Cardiol 28 (1996): 1556-61
  26. Tsai WC, Tsai LM, Chen JH "Combined use of astemizole and ketoconazole resulting in torsade de pointes." J Formos Med Assoc 96 (1997): 144-6
  27. "Product Information. Viracept (nelfinavir)." Agouron Pharma Inc PROD (2001):
  28. Ament PW, Paterson A "Drug interactions with the nonsedating antihistamines." Am Fam Physician 56 (1997): 223
  29. Jurima-Romet M, Crawford K, Cyr T, Inaba T "Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals." Drug Metab Dispos 22 (1994): 849-57
  30. Rankin AC "Non-sedating antihistamines and cardiac arrhythmia." Lancet 350 (1997): 1115-6
  31. Gonzalez MA, Estes KS "Pharmacokinetic overview of oral second-generation H-1 antihistamines." Int J Clin Pharmacol Ther 36 (1998): 292-300
  32. "Product Information. Agenerase (amprenavir)." Glaxo Wellcome PROD (2001):
  33. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  34. "Product Information. Fortovase (saquinavir)." Roche Laboratories PROD (2001):
  35. Mangum EM, Graham KK "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy 21 (2001): 1352-63
  36. DuBuske LM "Second-generation antihistamines: the risk of ventricular arrhythmias." Clin Ther 21 (1999): 281-95
  37. "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb (2003):
  38. "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline (2003):
  39. "Product Information. Prezista (darunavir)." Ortho Biotech Inc (2006):
View all 39 references

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Moderate

ritonavir tenofovir

Applies to: AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir) and AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

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

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

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Moderate

lopinavir tenofovir

Applies to: AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir) and AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

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

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

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Drug and food interactions

Major

astemizole food

Applies to: Hismanal (astemizole)

GENERALLY AVOID: Some beverages such as tonic water contain varying amounts of quinine. Coadministration of a single 430 mg dose of quinine has been shown to increase plasma concentrations of astemizole and its metabolite, desmethylastemizole. Elevated levels of these agents may cause a prolongation of the electrocardiographic QT interval and potentially fatal ventricular arrhythmias. Although pharmacokinetic data have indicated that the amounts of quinine in beverages (up to 80 mg quinine in 32 oz of tonic water) are not sufficient to produce a significant effect, the potential for an interaction exists if large amounts of tonic water are ingested. Also, grapefruit juice has been shown to inhibit CYP450 enzymes, which may lead to increased serum astemizole concentrations. The risk of life-threatening ventricular arrhythmias may be increased.

MANAGEMENT: Patients should be counseled to limit consumption of quinine-containing beverages and avoid grapefruit juice while they are taking astemizole.

References

  1. "Product Information. Hismanal (astemizole)." Janssen Pharmaceuticals PROD (2002):

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Moderate

ritonavir food

Applies to: AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

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. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):

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Moderate

lopinavir food

Applies to: AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

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. "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical PROD (2001):

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Minor

tenofovir food

Applies to: AccessPak for HIV PEP Expanded with Kaletra (emtricitabine / lopinavir / ritonavir / tenofovir)

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. "Product Information. Viread (tenofovir)." Gilead Sciences (2001):

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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.

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