1479CHAPTER 124 Adverse Drug Reactions and Drug Drug Interactions increase sensitivity to vasopressor effects When adding linezolid to vasopressor therapy, a reduction in dosing may be needed based on[.]
CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions increase sensitivity to vasopressor effects When adding linezolid to vasopressor therapy, a reduction in dosing may be needed based on hemodynamic response.146 Antihistamines, such as diphenhydramine, inhibit tissue uptake of epinephrine and norepinephrine while also increasing adrenoreceptor sensitivity to epinephrine.171 Owing to the short half-life of most vasoactive continuous infusions, ADEs associated with DDIs can be addressed quickly with careful titration to desired effect Antiarrhythmics Medications used to treat arrhythmias are associated with multiple pharmacodynamic and pharmacokinetic DDIs, necessitating close monitoring in critically ill patients Pharmacodynamic interactions with drugs that modulate AV nodal conduction may produce clinically significant adverse effects, which can include heart block, bradycardia, and other arrhythmias Disopyramide, procainamide, flecainide, amiodarone, and sotalol are antiarrhythmic agents that can prolong the QT interval When combined with other agents that prolong the QT interval, an additive effect can be seen, with an increased risk of TdP (see Box 124.2) Review of resources, such as www.crediblemeds.org, may be helpful in determining the risk of these combinations and possible alternatives.71 Amiodarone, flecainide, and sotalol decrease heart rate and can lead to severe bradycardia if combined with other negative inotropes, such as b-blockers, non-DHP CCBs, and ivabradine The antiarrhythmic drugs amiodarone, disopyramide, and quinidine are substrates for CYP3A4 Plasma levels of these antiarrhythmics may increase and produce adverse effects when combined with CYP3A4 inhibitors such as macrolide antibiotics, azole antifungals, and other miscellaneous inhibitors such as cyclosporine, non-DHP CCBs such as diltiazem and verapamil, and grapefruit juice Conversely, plasma levels decrease when therapy is combined with drugs that are known enzyme inducers, which include phenobarbital, carbamazepine, phenytoin, oxcarbazepine, and rifampin The antiarrhythmic drugs flecainide and mexiletine are substrates for CYP2D6 Concomitant therapy with enzyme inhibitors of CYP2D6—including amiodarone, diphenhydramine, fluoxetine, haloperidol, and quinidine—could result in toxicity.66,67 Amiodarone, also metabolized by the CYP1A2 and CYP2C isoenzymes as well as CYP3A4, has a significant interaction with rifampin When combined with rifampin, amiodarone and its active metabolite concentrations may be decreased by more than 50%, necessitating an increased dose and close monitoring to avoid precipitating dangerous arrhythmias.172 As a substrate for PgP, digoxin exhibits reduced renal and nonrenal clearance when a PgP inhibitor is added to the drug regimen Plasma levels of digoxin may increase 100% to 200%, demanding close monitoring for digoxin toxicity PgP inhibitors include amiodarone, clarithromycin, cyclosporine, diltiazem, erythromycin, ketoconazole, itraconazole, and verapamil.66,67 Patients with severe electrolyte imbalances may be susceptible to digoxin toxicity Hypokalemia, hypomagnesemia, and hypercalcemia are all conditions that may be drug induced Therefore, drugs may interact with digoxin in an indirect manner through alteration of electrolyte homeostasis Loop diuretics, thiazide diuretics, amphotericin B, corticosteroids, laxatives, and sodium polystyrene sulfonate may all contribute to digoxin toxicity.171 b-Blockers b-Blockers may be used in PICU patients to attenuate heart rate, control elevated blood pressure, or treat symptoms associated with congenital heart defects Digoxin and non-DHP CCBs increase 1479 the risk of additive bradycardia when combined with b-blockers.173 Combining b-blocking agents with amiodarone has also been associated with significant, potentially fatal, bradycardia, which is more likely with hepatically metabolized b-blockers (metoprolol and propranolol).174 However, it is recommended to follow patients closely when the combination of amiodarone and any b-blockers is required.173 The use of nonselective b-blockers and clonidine may be necessary in patients with resistant hypertension However, abrupt withdrawal of the a-antagonist clonidine increases the risk of significant rebound hypertension owing to unopposed a-activity Using cardioselective b-blockers (metoprolol, atenolol) or agents with a- and b-blocking properties, such as labetalol, can minimize the risk of this ADE.175 The combination of b-blockers and b-agonists, such as al buterol or terbutaline, may be unavoidable in PICU patients Nonselective b-blockers, such as propranolol, increase the risk of bronchoconstriction in patients with reactive airway disease, counteracting the effects of b-agonist bronchodilators Conversely, b-agonists can increase heart rate and decrease effectiveness of b-blockers.176 If this combination cannot be avoided, it is recommended to use the lowest effective dose of the bronchodilating agent and consider cardioselective b-blocking agents to decrease risk of additive bronchoconstriction As mentioned previously, levalbuterol may be an alternative bronchodilating agent that has less effect on heart rate However, there has been limited evidence to support its benefit The antihypertensive effect of bblockers may be minimized by long-term NSAID use NSAIDs inhibit prostaglandin production, which can increase blood pressure If NSAID use is necessary for a patient on a b-blocking agent, therapy should be limited to shorter durations.177 Pharmacokinetically, fluoxetine, paroxetine, and sertraline, SSRIs used for depression, inhibit CYP2D6, increasing concentrations of hepatically eliminated b-blockers such as propranolol, metoprolol, and carvedilol Lower doses of b-blocking agents or a switch to a renally cleared b-blocker, such as atenolol, may decrease the risk of bradycardia associated with this interaction Alternative antidepressants that are not CYP2D6 inhibitors may also be considered to avoid this interaction when starting therapy in the PICU.178 Calcium Channel Blockers Calcium channel antagonists have been implicated in several common pharmacokinetic drug-drug interactions involving the CYP3A4 substrates Inducers of CYP3A4 are implicated in the reduced efficacy of calcium channel antagonists.179 These include nafcillin, rifampin, bosentan, fosphenytoin, phenytoin, and phenobarbital.173 Alternative agents or increased doses of CCBs may be necessary to prevent treatment failure Agents that inhibit CYP3A4 metabolism—such as macrolide antibiotics, azole antifungals, and grapefruit juice—increase concentrations of CCBs and may potentiate the effects Angiotensin-Converting Enzyme Inhibitors ACE inhibitors have been implicated in a variety of drug-drug interactions mainly associated with electrolyte disturbances Potassium-sparing diuretics, such as spironolactone and eplerenone, in combination with ACE inhibitors increase serum potassium levels.180 It is important to note that aspirin may decrease the effectiveness of ACE inhibitors Mechanistically, they have antagonistic effects on prostaglandin production However, some studies suggest that this interaction is only of concern with higher daily doses of aspirin.173 There is an interesting interaction between 1480 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology ACE inhibitors and allopurinol, a medication that may be used in oncology patients in the PICU Severe hypersensitivity reactions—including fever, arthralgia, myalgia, and fatal StevensJohnson syndrome—have been reported with this combination Though the mechanism is largely unknown, it is recommended to avoid this combination when possible.181 Nitrates The combination of nitrate vasodilators and sildenafil may result in significant hypotension Studies have shown sildenafil to be effective in treatment of pulmonary hypertension and chronic lung disease in pediatric and neonatal critical care.182,183 The increased use of this medication, especially in cardiac patients, has necessitated heightened surveillance of potential interactions Additionally, sildenafil is metabolized by cytochrome P450-3A4 enzymes, which can cause significant interaction potential with CYP3A4 inhibitors Concentrations of sildenafil have been increased by as much as 182% when combined with erythromycin.184 It is recommended to monitor patients closely for increased hypotensive effects of sildenafil if concomitant administration of CYP3A4 inhibitors, such as macrolide antibiotics or azole antifungals, cannot be avoided Anticonvulsant Medications The antiepileptics constitute a drug class that has the potential to be involved in a large array of DDIs These interactions are mainly pharmacokinetic in nature and usually involve induction, inhibition, or competition among substrates for various isoforms of the cytochrome P450 enzyme system Fortunately, many of these drugs can be monitored using targeted blood concentrations, which can aid in the avoidance of adverse events secondary to DDIs Table 124.4 lists the isoforms for which the various antiepileptics are substrates, inducers, or inhibitors In the ICU setting, phenytoin is generally administered intravenously in the form of the water-soluble prodrug fosphenytoin Phosphatases in red blood cells and the liver catalyze the conversion of fosphenytoin to its active form phenytoin Fosphenytoin has a serum half-life of to 15 minutes Once fosphenytoin is converted to phenytoin, it is susceptible to all of the potential DDIs that affect orally administered phenytoin Approximately 95% of phenytoin is metabolized in the liver by the CYP2C9/10 and CYP2C19 isoforms of the cytochrome P450 system Phenytoin metabolism is reduced and plasma levels increased via competition with other drugs that are substrates for CYP2C9 and CYP2C19, such as amiodarone, fluconazole, valproic acid, omeprazole, and fluoxetine Conversely, phenytoin may competitively inhibit the metabolism of these drugs Drugs that inhibit CYP2C9 reduce clearance of phenytoin and, consequently, increase plasma concentrations Examples include fluconazole, cotrimoxazole, amiodarone, and valproate Omeprazole, cimetidine, and fluoxetine are inhibitors of CYP2C19 and thus can increase phenytoin plasma concentrations In addition to serving as a substrate to CYP2C9/10 and CYP2C19, phenytoin can also induce their activity Phenytoin exhibits a high degree of protein binding (90%); therefore, displacement from its binding sites may produce clinically significant changes in the active free phenytoin concentration Owing to fluctuations in protein status, populations who may be at risk for DDIs associated with elevated free phenytoin levels include neonates, patients with uremia, hyperbilirubinemia, or hypoalbuminemia Phenobarbital is a substrate for CYP2C9, CYP2C19, and CYP2E1 The CYP2C19 isoform serves as the primary pathway for metabolism Phenobarbital has the potential to induce CYP2C9 and CYP3A4 enzymes The time frame for induction and deinduction of the P450 enzyme system depends on phenobarbital’s half-life, with induction beginning week after initiation of phenobarbital therapy and deinduction beginning week after phenobarbital is discontinued Maximum induction occurs in approximately to weeks As an example, the addition of phenobarbital or phenytoin to a regimen of methadone could lead to a significant DDI Induction of CYP2C9 and CYP3A4 leads to increased clearance of methadone, increasing the possibility of methadone withdrawal In transplant patients, phenobarbital may reduce cyclosporine concentrations, affecting immunosuppression levels and, potentially, long-term graft survival Oxcarbazepine undergoes extensive metabolism through the liver to an active metabolite Oxcarbazepine is a weak inhibitor of CYP2C19 and strong inducer of CYP3A4/5 isoforms When oral contraceptives, dihydropyridine calcium antagonists, and cyclosporine are given concomitantly with oxcarbazepine, decreased drug levels were shown due to the induction of CYP3A4/5 isoforms Valproate inhibits drugs that are metabolized by CYP2C9, such as phenytoin and phenobarbital More specifically, valproic acid inhibits drugs that are metabolized by uridine 59-diphosphate glucuronosyltransferases (UGTs), such as lorazepam and lamotrigine Valproic acid also exhibits a high degree of protein binding to plasma albumin (90%), making protein displacement interactions likely with other highly protein-bound drugs The main pathway for metabolism of lamotrigine is UGTmediated glucuronidation Lamotrigine can induce its own metabolism, with maximum autoinduction observed within weeks Autoinduction typically results in a 17% reduction in plasma blood levels Through their action on UGT, carbamazepine, phenytoin, and phenobarbital reduce plasma concentrations of lamotrigine when given concomitantly Lamotrigine, on the other hand, reduces valproic acid plasma levels by as much as 25% in the course of a few weeks of therapy Levetiracetam is a fairly new anticonvulsant that has seen increased use owing to its noninferiority compared with other anticonvulsants and limited side effect profile.185 Levetiracetam does not undergo metabolism through cytochrome P450 enzymes in the liver and therefore has limited drug interactions.186 Antiinfective and Antimicrobial Agents Antimicrobial agents are commonly used in the ICU to treat patients with serious infections Many DDIs involve antimicrobial agents Complexation of fluoroquinolones (ciprofloxacin, levofloxacin) to multivalent cations (aluminum, calcium, magnesium, and iron) due to binding within their chemical structures is an example of an interaction that can be easily managed by administering the drugs at separate times Macrolide antibiotics are associated with many DDIs that can be of clinical importance Erythromycin may cause interactions through inhibition of the CYP3A4 enzyme, which can increase serum levels of warfarin, cyclosporine, midazolam, and tacrolimus Clarithromycin also inhibits cytochrome P450 enzymes and may increase the serum levels of carbamazepine, caffeine, cyclosporine, warfarin, valproate, and midazolam Azithromycin does not demonstrate cytochrome P450 complexation; thus, it has less drug interaction potential Carbapenems are commonly used in the ICU for treatment of gram-negative sepsis Though not commonly associated with CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions significant DDIs, concurrent use of carbapenems with valproic acid and its derivatives can cause a significant and sudden decrease of valproate serum concentrations The effect is most significant with meropenem, in which a decrease of up to 90% in valproic acid levels can be observed This interaction can persist for weeks, even upon discontinuation of the carbapenem In patients who need valproic acid for primary prevention of seizures, use of carbapenems is discouraged However, if no substitute is available, the addition of a second antiepileptic agent should be considered to control seizures and prophylaxis Oritavancin—a novel lipoglycopeptide antibiotic with emerging use in pediatrics for skin and soft-tissue infections caused by gram-positive organisms, including MRSA—has several unique drug-drug and drug-laboratory interactions Oritavancin has an ability to bind to phospholipid reagent, preventing the activation of coagulation in laboratory tests.187 Owing to its long half-life, oritavancin can artificially prolong activated partial thromboplastin time up to 120 hours, prothrombin time/international normalized ratio for 12 hours, and activated clotting time for 24 hours In patients requiring coagulation test monitoring, a chromogenic factor Xa assay should be considered.187 Many anticoagulants, including warfarin and heparin, should be dosed cautiously while using oritavancin Rifampin is a cytochrome P450 enzyme inducer that is involved in many DDIs Rifampin may decrease serum concentrations of isoniazid, amiodarone, cyclosporine, prednisolone, and warfarin These interactions often complicate multidrug regimens for treatment of endocarditis, active tuberculosis, or nontuberculous mycobacteria Additionally, drug levels of azole antifungals— especially itraconazole, voriconazole, and posaconazole—may be rendered undetectable when used in conjunction with strong P450 enzyme inducers such as rifampin Alternative antifungal agents should be considered in situations in which rifampin cannot be discontinued Antifungal agents are used in the critical care setting for treatment and prophylaxis of systemic mycoses Azole antifungals, including the new novel azole isavuconazonium, are known inhibitors of cytochrome P450 isoenzymes, although the specific CYP isoforms and potency of inhibition vary among agents.122 Table 124.4 describes cytochrome P450 isoforms inhibited by the azole antifungals Clinically significant interactions with azoles occur most frequently with agents that have narrow therapeutic windows and are metabolized by cytochrome P450 enzymes Additionally, significant interactions can occur when azole derivatives are administered with CYP3A substrates such as midazolam, tacrolimus, sirolimus, cyclosporine, nifedipine, felodipine, diltiazem, and alfentanil Oral absorption of itraconazole and posaconazole is pH dependent and may result in a clinically significant decrease in therapeutic efficacy if these agents are used concurrently with proton pump inhibitors or H2-antagonists This interaction is more pronounced with the liquid formulations of the medications Echinocandins are increasingly used in the treatment of fungal infections owing to their relatively safe side effect profile and lack of cytochrome P450 and PgP-mediated drug interactions Anesthetic Agents and Sedatives Several agents are used for anesthesia and sedation in the pediatric critical care setting, including many that have clinically significant drug interactions Overall, the ability to recognize potential interactions for these drugs requires a fundamental understanding of the agents’ clinical pharmacology For example, benzodiazepines 1481 are a class of sedatives that are particularly susceptible to DDIs because of their metabolism by cytochrome P450.188 CYP3A4 plays a major role in the metabolism of midazolam, diazepam, and clonazepam; caution should be exercised when combining these agents with CYP3A modulators Midazolam, a short-acting benzodiazepine commonly used in the pediatric critical care setting, is almost exclusively metabolized by CYP3A4 Interactions are also more prominent with oral midazolam therapy, since P450 enzymes in the upper GI tract will immediately deactivate some of the drug via first-pass metabolism.189 Diazepam, a long-acting benzodiazepine, is also metabolized by CYP2C19 and is thus prone to DDIs with inhibitors or inducers of both CYP2C19 and 3A4 Lorazepam, however, undergoes direct hepatic conjugation and therefore is not affected by the cytochrome P450 system.188 Overall, caution should be exercised when benzodiazepines are used concomitantly with known CYP3A inhibitors, such as azole antifungals and macrolide antibiotics, or inducers, such as rifampin and phenytoin, due to this known DDI Dexmedetomidine is another common sedative medication used in the pediatric critical care setting It is an a2-adrenergic agonist that undergoes hepatic metabolism by N-glucuronidation, N-methylation, and CYP2A6-mediated hydroxylation Fortunately, no clinically significant cytochrome P450 drug interactions have been identified, but the effects of dexmedetomidine may be potentiated by other CNS depressants In addition, vasodilators or negative chronotropic agents may cause additive hypotensive or bradycardic effects when used concurrently with dexmedetomidine.189 In general, pharmacodynamic drug interactions are highly likely with sedative agents Given that these drugs target the CNS, they can interact with other CNS depressants (e.g., opioids, barbiturates, propofol) to cause additive CNS depression Opioids and benzodiazepines are often used synergistically in clinical practice, but caution should still be used when appropriate Of note, flumazenil can be used in the setting of a benzodiazepine overdose by inhibiting the activity of benzodiazepines at the receptor site on the g-aminobutyric acid (GABA)-benzodiazepine receptor complex However, it does not reverse the CNS effects of GABAmimetic agents such as barbiturates, propofol, and other general anesthetics.190 Last, neuromuscular blocking agents (NMBAs) are prone to several DDIs Overall, interacting drugs can either potentiate or antagonize neuromuscular blockade Aminoglycosides, furosemide, CCBs, and clindamycin can enhance blockade owing to their activity at the neuromuscular junction Inhalation anesthetics also potentiate neuromuscular blockade by decreasing the sensitivity of the neuromuscular junction to acetylcholine On the other hand, phenytoin and acetylcholinesterase inhibitors may diminish the neuromuscular-blocking effects of NMBAs.191 Analgesic Agents A variety of opioid analgesics are used for pain and sedation in the pediatric critical care setting, making patients particularly susceptible to drug interactions As previously mentioned, whenever an opiate agonist is concomitantly administered with a CNS depressant, augmented effects or toxicity is possible Therefore, vigilant monitoring for drug interactions is necessary to ensure that safe and effective analgesia is achieved Like anesthetic and sedative agents, analgesics are prone to pharmacokinetic drug interactions For example, methadone, oxycodone, and fentanyl all undergo cytochrome P450 phase I 1482 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology metabolism via CYP3A4 As a result, they are prone to drug interactions with CYP3A4 inhibitors (e.g., azole antifungals, antiretrovirals, ciprofloxacin, erythromycin) and inducers (e.g., phenobarbital, phenytoin, carbamazepine, valproic acid), which can increase or decrease drug concentrations, respectively.192–194 Morphine is metabolized by hepatic glucuronidation with negligible P450 enzyme metabolism.193 The enzymes UGT1A3 and UGT2B7 are responsible for creating the conjugates morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G), with M6G as the active and much more potent metabolite However, M6G is produced to a lesser extent (15%) compared with M3G (55%).195 Compared with CYP450 enzymes, clinical data is limited on drug interactions with UGT enzymes As a result, UGT enzyme inhibitors/inducers cause minimal pharmacokinetic changes to morphine and its conjugates.167,195 Similar to morphine, hydromorphone is also primarily metabolized by glucuronidation via UGT1A3 and UGT2B7 to inactive metabolites Since it has minimal CYP450 metabolism, clinically significant pharmacokinetic DDIs are unlikely.195 Pharmacodynamic drug interactions can also result in opioid synergy or antagonism When a pure opiate agonist, partial agonist, or an antagonist is used in combination, there is a risk for decreased clinical effects For example, when morphine (a pure m-opioid agonist) and nalbuphine (a partial opioid agonist/antagonist) are used in combination, it can result in a decreased opiate effect This can negatively impact analgesia and may result in withdrawal symptoms for patients on long-term opioid therapy Overall, opioids are associated with several side effects, including respiratory depression, hypotension, decreased GI motility, nausea, and vomiting, which can be heightened by DDIs However, if severe ADRs occur, naloxone, a pure opioid antagonist, is available for reversal of undesirable effects Anticoagulants Warfarin is involved in a multitude of DDIs through a variety of mechanisms, including alterations in protein binding, cytochrome P450 activity, disruption of bacterial flora in the GI tract, and fluctuations in the clotting cascade (Table 124.6) Aspirin, chloral hydrate, ibuprofen, and sulfamethoxazole can displace warfarin from protein-binding sites, increasing free fraction of warfarin available and, hence, augmenting anticoagulation Warfarin metabolism may be inhibited by amiodarone, sulfamethoxazole, metronidazole, azole antifungals, isoniazid, and macrolide and quinolone antibiotics, resulting in decreased effect.196 Phenobarbital, TABLE 124.6 Medication Interactions That Modify Anticoagulant Effect of Warfarin Increased INR Decreased INR Increased Risk of Bleeding Increased Risk of Thrombosis CYP450 Inhibition via 2C9 CYP450 Induction via 2C9 (unless otherwise noted) (unless otherwise noted) Bosentan Carbamazepine Phenobarbital Phenytoin Rifampin Alterations in Platelet Function Antiplatelet Agents: Alterations in Warfarin Metabolism or Absorption Aspirin Clopidogrel Ticlopidine Cimetidine Fat emulsion (fish oil based) Fish oil Cholestyramine Griseofulvin Nafcillin Ribavirin Sucralfate Antidepressants: Fluvoxamine Sertraline Antiinfectives: Azole antifungals (2C9/3A4) Cotrimoxazole Fluoroquinolones (1A2/3A4) Isoniazid Macrolides Metronidazole Miconazole Cardiovascular Drugs: Amiodarone Fluvastatin Gemfibrozil Lovastatin Simvastatin Antifibrinolytics: Alteplase Streptokinase Urokinase NSAIDs: Aspirin Ibuprofen Indomethacin Ketorolac Prothrombotic Estrogens OCPs Phytonadione Total parenteral nutrition Multivitamins/supplements with vitamin K SSRIs: Citalopram Sertraline Reduced Vitamin K Production Antiinfectives (oral) Esomeprazole Omeprazole Miscellaneous Acetaminophen (higher doses/longer durations)199 Corticosteroids Ethacrynic acid Levothyroxine Propranolol INR, International normalized ratio; NSAIDs, nonsteroidal antiinflammatory drugs; OCPs, oral contraceptive pills; SSRIs, selective serotonin reuptake inhibitors Modified from Hansten PD Oral anticoagulants and drugs which alter thyroid function Drug Intell Clin Pharm 1980;14:331–334; Liu A, Stumpo C Warfarin drug interactions among older adults Geriatrics Aging 2007;10(10):643–646; and Holbrook AM, Pereira JA, Labris R, et al Systematic overview of warfarin and its drug and food interactions Arch Intern Med 2005;165(10):1095–1106 CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions rifampin, and phenytoin can induce the metabolism of warfarin and decrease its effect dramatically Most antibiotics have the potential to decrease synthesis of vitamin K-dependent clotting factors and potentiate warfarin effects.196,197 Other medications, including NSAIDs and antiplatelet medications, can exacerbate the adverse effects of warfarin by directly affecting the clotting cascade Phytonadione (vitamin K), often found in total parenteral nutrition (TPN), multivitamins, and supplements, antagonizes the anticoagulant effect of warfarin.198 Careful monitoring of coagulation levels and clinical presentation can help prevent serious ADRs Many DDIs can occur when initiating warfarin therapy or when adding other medications to existing warfarin therapy It is strongly recommended to use adjusted starting doses of warfarin in initiating therapy when patients are receiving medications with potential for interaction Heparin interacts with other agents, which can increase the risk of bleeding or thrombosis by attenuating heparin’s effect Common interactions include oral anticoagulants and platelet inhibitors, such as aspirin, dextran, ibuprofen, and other agents that interfere with platelet aggregation Heparin effectiveness can also be altered by the administration of additional clotting factors found in fresh frozen plasma and antithrombin III More recently, antifibrinolytic agents—such as tissue plasminogen activator (tPA), which enhances the anticoagulant effects of heparin—have become one of the primary interventional therapies for clinically significant thromboses Though concomitant anticoagulation with heparin is often indicated with antifibrinolytic agents and blood products, it is important to adjust heparin infusion rates and monitor therapeutic response when combining these medications Enoxaparin and other low-molecular-weight heparins have similar interactions with medications independently associated with an increased risk of bleeding, as mentioned earlier.200 Additionally, medications that adversely affect renal clearance can prolong the elimination half-life of enoxaparin and increase the risk of adverse effects.200 There are many newer oral anticoagulants on the market, mostly used in adults, that are currently being studied in pediatric patients Limited data is available for dosing and monitoring However, as they may become more prevalent in this population, it is important to be aware of possible DDIs (see Table 124.4) Dabigatran, an enteral direct thrombin inhibitor, and the oral anti–factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have interactions with PgP inhibitors such as rifampin All but edoxaban and dabigatran can interact with strong CYP3A4 inhibitors, such as azole antifungals and macrolides Additionally, dabigatran may interact with certain proton pump inhibitors Dose reduction or modification of medication therapy may be required As with other anticoagulants, close monitoring is required when using with antiplatelet agents or other medications noted to increase risk of bleeding.201,202 Immunosuppressive Agents Most immunosuppressive agents possess narrow therapeutic indices and therefore require therapeutic drug monitoring.203 As a result, a sophisticated knowledge of clinical pharmacology is required to evaluate the clinical relevance of potential DDIs involving these drugs DDIs most commonly encountered with immunosuppressive drug therapy revolve around the inhibition or induction of the CYP3A enzymes Cyclosporine, tacrolimus, prednisone, sirolimus, and everolimus are all CYP3A substrates and are most prone to these types of pharmacokinetic DDIs 204,205 Interestingly, known CYP3A inhibitors, such as ketoconazole, have 1483 been used intentionally to maintain therapeutic levels in patients with high presystemic metabolism of cyclosporine.206 Medications that inhibit CYP3A metabolism should be used with caution in patients taking cyclosporine, tacrolimus, sirolimus, or everolimus However, if concomitant use cannot be avoided, dosing adjustments of immunosuppressive therapy may be required, and therapeutic drug level should be monitored closely Table 124.4 provides a list of medications that are CYP3A4 enzyme inhibitors Invasive fungal infections are a major concern in patients undergoing solid-organ or hematopoietic stem cell transplant Therefore, it is not uncommon for these patients to require triazole antifungal therapy All triazole antifungal agents inhibit CYP3A4 at varying degrees and have the potential to reduce the metabolism of cyclosporine, tacrolimus, sirolimus, and everolimus According to the voriconazole labeling information, the steady-state dose of cyclosporine and tacrolimus should be reduced by 50% and 67%, respectively, when voriconazole is initiated.207 While it also states that coadministration with sirolimus is contraindicated, studies suggested that a 90% reduction in sirolimus dose could be used safely with voriconazole.112,208 The addition of posaconazole necessitates a 25% decrease in cyclosporine dose and a 67% decrease in tacrolimus dose in patients who are maintained on a steady dose of the immunosuppressants.207 Similar to voriconazole prescribing information, coadministration of posaconazole with sirolimus is contraindicated However, several studies demonstrated a reduction in posaconazole dose by at least 50% to 65% allowed for maintenance of sirolimus level within therapeutic range.209,210 As compared with either voriconazole or posaconazole, fluconazole is a less potent inhibitor and interaction is dose dependent A significant increase in immunosuppressant exposure may still be expected but likely to a lesser degree Concomitant administration of sirolimus or everolimus with cyclosporine increases sirolimus and everolimus exposure, likely due to shared CYP3A and PgP metabolic pathways.211,212 Several drugs can induce the metabolism of cyclosporine, tacrolimus, sirolimus, everolimus, and prednisone Rifampin causes induction of CYP3A and PgP, leading to clinically significant decreases in cyclosporine and tacrolimus plasma concentrations.213,214 Although not considered to have a narrow therapeutic index, mycophenolate serum concentrations are affected by concurrent administration with cyclosporine Cyclosporine decreases enterohepatic recirculation of mycophenolic acid, necessitating higher mycophenolate doses to achieve serum concentrations equivalent to that of the drug given alone or with tacrolimus.215 This interaction may be overcome by using enteric-coated mycophenolic acid formulations.216 Azathioprine, an older immunosuppressant, is a prodrug of mercaptopurine Its biotransformation is dependent on the thiopurine-S-methyltransferase (TPMT) enzyme, xanthine oxidase, and inosine monophosphate dehydrogenase There are genetic polymorphisms of the TPMT enzyme that may predispose heterozygous and homozygous carriers of the gene to increased bone marrow toxicities with increased levels of the cytotoxic thioguanine metabolite.217 Concurrent use of allopurinol, a xanthine oxidase inhibitor, can increase systemic mercaptopurine exposure and toxicity Therefore, a dose reduction of 65% to 75% is recommended to decrease risk of toxicity.218 Antineoplastic Agents The majority of DDIs in patients receiving chemotherapy involve the cytochrome P450 enzyme system Potential interactions can be identified by pinpointing the substrates for the various ... fatal StevensJohnson syndrome—have been reported with this combination Though the mechanism is largely unknown, it is recommended to avoid this combination when possible.181 Nitrates The combination... that of the drug given alone or with tacrolimus.215 This interaction may be overcome by using enteric-coated mycophenolic acid formulations.216 Azathioprine, an older immunosuppressant, is a prodrug... is a prodrug of mercaptopurine Its biotransformation is dependent on the thiopurine-S-methyltransferase (TPMT) enzyme, xanthine oxidase, and inosine monophosphate dehydrogenase There are genetic