Clinimix E 5%/D20w Sulfit Free (amino acid 5 % comb no.6/dextrose 20 %/electrolyte no.23)

Dosage of dextrose depends on the age, weight, clinical condition, and fluid, electrolyte, and acid-base balance of the patient. Dextrose may usually be administered IV to healthy individuals at a rate of 0.5 g/kg per hour without producing glycosuria; the maximum infusion rate should generally not exceed 0.8 g/kg per hour.

For the treatment of hypoglycemia resulting from insulin excess or other causes in adults and children, the usual dose is 20-50 mL of 50% dextrose injection administered slowly (e.g., 3 mL/minute) IV; repeated doses and supportive therapy may be required in severe cases. For the treatment of acute symptomatic hypoglycemia in neonates and infants, the usual dose is 2 mL/kg of 10-25% dextrose injection administered slowly IV; higher or repeated doses may be required in severe cases, and subsequent continuous IV infusion of 10-15% dextrose injection may be necessary to maintain sufficient blood glucose concentrations. When patients do not respond to or tolerate dextrose, the use of other drugs (e.g., glucagon, corticosteroids, epinephrine) should be considered.

For the management of hypoglycemia in conscious diabetics, 10-20 g of dextrose may be administered orally as a gel or chewable tablets; the dose may be repeated in 10-20 minutes if necessary. Self monitoring of blood glucose concentration may be useful in determining whether a repeat dose is necessary; some clinicians recommend that if hypoglycemic symptoms are still present and a blood glucose increase of at least 20 mg/dL is not achieved within 20 minutes after oral administration of dextrose, the patient should consider administration of a repeat dose. Each gram of the 40% (w/w) dextrose gel provides 400 mg of dextrose (i.e., 25 g of gel provides 10 g of dextrose).

For further information on chemistry and stability, pharmacology, uses, cautions, and dosage and administration of dextrose, specialized references and the manufacturers'; labeling should be consulted.

Dextrose injections are administered IV. Hypertonic dextrose solutions are preferably administered via an IV catheter placed into a large central vein. If hypertonic (10%) dextrose solutions are administered peripherally, a large arm vein should be used and, if possible, the injection site should be alternated daily. Except in the emergency treatment of severe hypoglycemia, higher concentrations of dextrose injections (e.g., 20% and higher) should be administered via central veins and only after appropriate dilution. When used for the emergency treatment of hypoglycemia, hypertonic dextrose injections may be administered slowly via a peripheral vein.

Concentrated dextrose gels and chewable dextrose tablets are administered orally in the management of acute symptomatic hypoglycemia.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Mixed & Indirect Sympathomimetics; Oral Phenylephrine/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine).

CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of monoamine oxidase inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic.

DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Linezolid is another antibacterial with monoamine oxidase inhibitor properties. Metaxalone is a weak inhibitor of MAO. Foods containing large amounts of tyramine have also been implicated in this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. At recommended dosages, rasagiline, oral selegiline, and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Sedative Hypnotics; Alcohol/Sodium Oxybate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Oxybate may be associated with respiratory depression. As oxybate is taken at bedtime, concurrent use with alcohol or hypnotics may increase the risk for respiratory depression or loss of consciousness.(1-3) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for respiratory depression and profound sedation or coma.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: The FDA states that sodium oxybate is contraindicated in patients also taking hypnotics or alcohol.(1,2) Significant quantities of alcohol may be present in medicinal products. Alcohol is is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (4): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended upward dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Serotonergic Agents/Dapoxetine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Tryptophan/Mao Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive effects on serotonin levels. MAOIs may potentiate the effects of tryptophan.(1)

CLINICAL EFFECTS: Concurrent administration of tryptophan with a MAO Inhibitor may result in serotonin syndrome and/or hypertensive crisis.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(15) In addition to these effects, disorientation, delirium, agitation, hypomania, shivering, ocular oscillation, and Babinski signs have been reported with concurrent tryptophan and phenelzine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving MAO Inhibitors should not take agents such as tryptophan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study in nine subjects, the administration of a single intravenous dose of tryptophan with tranylcypromine significantly increased the normal prolactin response to tryptophan. Four of the nine subjects developed a distinctive neuromotor syndrome characterized by hyperreflexia, ankle clonus, nystagmus, incoordination, tremor, myoclonic jerks, and nausea.(2) Another set of authors reported eight cases of delirium, ranging from mild to severe, in patients who received concurrent tranylcypromine and tryptophan. Symptoms developed within two days to 4 weeks of beginning concurrent therapy.(3) In a case report, the addition of tryptophan to a tranylcypromine regimen resulted in hypomania.(4) In another report, a patient developed hyperventilation, shivering, hyperthermia, increased muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine therapy.(5) There are two reports of fatalities following the concurrent administration of tryptophan and tranylcypromine. In the first report, a a patient had been receiving chlorpromazine, lithium, and tryptophan when phenelzine was initiated. Four weeks later, the patient developed neuroleptic malignant syndrome and expired despite resuscitation efforts.(6) In the second report, a patient had been receiving fluoxetine, levothyroxine, propranolol, quinidine, and hydroxyzine. Fluoxetine was discontinued and tranylcypromine, thioridazine, and tryptophan were initiated. The patient developed neuroleptic malignant syndrome two and one-half hours after the first tryptophan dose and expired 24 hours later. (7) In a case report, the addition of tryptophan to a regimen that included phenelzine resulted in an acute behavioral and neurologic syndrome. The patient's symptoms resolved 24 hours after the discontinuation of both agents.(8) In another report, a patient developed hypomania following the addition of tryptophan to phenelzine therapy.(4) Another report describes the development of delirium following the addition of tryptophan to phenelzine.(9) One set of authors reported three cases of myoclonus, hyperreflexia, and diaphoresis following the addition of tryptophan to phenelzine therapy.(10) Some studies have shown that the addition of tryptophan to MAO Inhibitor therapy may have beneficial results, including greater improvement in depression and faster onset of effects.(11,12) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(13,14) Metaxalone is a weak inhibitor of MAO.(16,17)

Tryptophan/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of sibutramine and tryptophan may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The UK manufacturer of sibutramine formerly stated that sibutramine should not be administered with other drugs that raise serotonin levels in the brain, such as tryptophan.(2) The US manufacturer of sibutramine formerly stated that in general, sibutramine should not be administered with other serotonergic agents such as tryptophan. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(1) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. There is no published documentation to support this interaction. Because sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and tryptophan, the UK manufacturer of sibutramine states that sibutramine should not be administered with tryptophan.(2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aspartame; Phenylalanine; Tyrosine/Nitisinone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aspartame contains phenylalanine, which is metabolized into tyrosine. Nitisinone prevents the breakdown of tyrosine.(1)

CLINICAL EFFECTS: Elevated levels of tyrosine can cause vision changes (cornea ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin problems (painful hyperkeratotic plaques on the soles and palms), and nervous system toxicity (variable degrees of mental retardation and developmental delay).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving nitisinone should following dietary restrictions concerning the consumption of aspartame, phenylalanine, and tyrosine, including medications that contain these ingredients.(1)

DISCUSSION: In most patients, eye symptoms resulting from elevated tyrosine levels were transient, lasting less than one week; however, six patients had prolonged episodes lasting up to almost 2 years.(1)

Intravenous Calcium Products/Digitalis Glycosides

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of action of digitalis glycosides involves its ability to cause an increase in excitation-contraction coupling mediated through the effects of calcium. Excitable tissues in the heart experience inhibition of sodium/potassium ATPase (the membrane "sodium pump") by digitalis glycosides and so attain relatively higher intracellular sodium and lower potassium concentrations. Higher intracellular sodium concentrations facilitate exchange of extracellular calcium ions and the inward and internal flux of calcium results in modified transmembrane potentials and stronger contractions of cardiac muscle. Elevated extracellular concentrations of calcium after parenteral calcium salts further facilitate these inward calcium fluxes.

CLINICAL EFFECTS: Rapid administration of calcium via the intravenous route may result in digitalis toxicity, including arrhythmias.(1)

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: In patients maintain on a digitalis glycosides, administer intravenous calcium slowly and with caution. If cardiac toxicity develops, supportive measures without additional antiarrhythmics may be sufficient.

DISCUSSION: Effects of digitalis glycosides on the heart are increased by elevated extracellular concentrations of ionic calcium. Intravenous administration of calcium salts during digitalis therapy may result in altered cardiac electrophysiologic activity such as tachycardia or arrhythmias. Oral calcium carbonate has not been shown to affect the bioavailability of oral digitalis.

Intravenous Calcium Products/Intravenous Ceftriaxone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Intravenous ceftriaxone and intravenous calcium may form an insoluble precipitate if administered too closely together.

CLINICAL EFFECTS: Intravenous administration of calcium-containing products with intravenous ceftriaxone may have serious risks in all patients, especially in the neonate population. NEONATES: Intravenous administration of calcium-containing products within 48(1-2) to 120(3) hours of intravenous administration of ceftriaxone may result in damage to the lungs and/or kidneys in neonates. Fatalities in neonates have been reported.(1-7) OLDER CHILDREN and ADULTS: Sequential administration requires proper line flushing. Use within 48 hours may result in the formation of kidney stones in older children(5) and the formation of "sludge" in the gallbladder.(2) Simultaneous administration in patients older than 28 days may result in the formation of an insoluble ceftriaxone-calcium precipitate.(1-7)

PREDISPOSING FACTORS: Neonates, both preterm and term, may be a greatest risk of death from this interaction.(1-4) Young age may predispose patients to formation of ceftriaxone-calcium precipitates in the kidney.(5) High doses of ceftriaxone may also increase the risk of precipitates.(6)

PATIENT MANAGEMENT: The US manufacturer of ceftriaxone, Health Canada, and the US Food and Drug Administration (FDA) state that the concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates less than or equal to 28 days of age. Ceftriaxone should not be used in neonates less than or equal to 28 days of age if they are receiving or are expected to receive calcium-containing intravenous products.(2,3,7) The US manufacturer of ceftriaxone, Health Canada, and the US FDA state that in patients older than 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid.(2,3,7) The US manufacturer of ceftriaxone, Health Canada, and the US FDA state that ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.(2,3,7)

DISCUSSION: Isolated reports of neonatal (both term and preterm infants) deaths have been associated with ceftriaxone-calcium precipitates in the lungs and kidneys. A total of 7 cases have been reported to the FDA, resulting in 5 deaths. All 5 deaths were in neonates of 3 weeks or less in age. Six of the 7 patients received calcium gluconate, 1 received calcium via hyperalimentation.(6) In some cases, ceftriaxone and the calcium product were administered by different routes,(1) lines,(2) and/or at different times.(1,2) Reports of a ceftriaxone-calcium salt precipitate in the gall-bladder have also been reported.(2) In in vitro studies in adult and neonatal plasma, ceftriaxone recovery was examined with ceftriaxone concentrations up to 1 mM (in excess of concentrations seen with 2 g ceftriaxone infused over 30 minutes) and calcium concentrations up to 12 mM (48 mg/dL). Ceftriaxone recovery was reduced with calcium concentrations of 6 mM (24 mg/dL) in adult plasma and 4 mM (16 mg/dL) in neonatal plasma. This may indicate ceftriaxone-calcium precipitation formation.(2,7) There have been no reports associated with concurrent use of oral calcium products and the US manufacturer of ceftriaxone states that there is no risk with oral calcium products or use of intramuscular ceftriaxone.(4)

Mixed & Indirect Sympathomimet;Oral Phenylephrine/Rasagiline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine).

CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Hypertensive crisis has been reported in patients taking recommended doses of rasagiline with sympathomimetic agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: At recommended dosages, rasagiline is selective for MAO-B; however, at higher dosages it has been shown to lose its selectivity. Patients receiving higher dosages of rasagiline should be considered susceptive to this interaction. Concurrent use should be approached with caution.

DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors.

Potassium Supplements/Eplerenone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eplerenone increases serum potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of eplerenone with a potassium supplement may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal impairment.

PATIENT MANAGEMENT: The manufacturer of eplerenone states that the use of eplerenone for the treatment of hypertension in patients receiving potassium supplements is contraindicated.(1)

DISCUSSION: The main risk of eplerenone therapy is hyperkalemia. The risk of hyperkalemia can be reduced by avoiding potassium supplements during eplerenone therapy.(1)

Potassium Supplements/Potassium Sparing Diuretics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Decreased renal excretion of potassium, resulting from administration of a potassium sparing diuretic.

CLINICAL EFFECTS: May observe hyperkalemia which may be severe or even fatal.

PREDISPOSING FACTORS: Renal function impairment.

PATIENT MANAGEMENT: If both drugs are administered, monitor potassium levels. Adjust the dose of the drugs accordingly. This combination should probably be avoided if possible.

DISCUSSION: The interaction is well documented. Patients with decreased renal function are especially at risk of developing hyperkalemia from this drug combination. A commonly held belief is that a potassium sparing diuretic formulated in combination with a thiazide diuretic, such as Dyazide, will not exhibit this interaction. Although the likelihood of hyperkalemia occurring may be reduced somewhat, a danger still exists.

Potassium Supplements/Trimethoprim

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Trimethoprim may increase serum potassium levels by reduction in potassium elimination.(1-3) The combination of trimethoprim and potassium supplements can have an additive effect on serum potassium resulting in potentially dangerous levels.

CLINICAL EFFECTS: Concurrent use of trimethoprim and potassium supplements may result in hyperkalemia, which may be severe.

PREDISPOSING FACTORS: Patients who are elderly, have any degree of renal insufficiency or heart failure have an increased risk for hyperkalemia.(1-9) Concomitant use with other drugs associated with hyperkalemia risk (e.g. ACE Inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, NSAIDs) and high doses of trimethoprim further increase the risk for hyperkalemia.(1-8) Interaction risk and severity is greater in patients with multiple risk factors.

PATIENT MANAGEMENT: Assure adequate monitoring for hyperkalemia.(1-9) Patients receiving trimethoprim and a potassium supplement concurrently should have their serum potassium monitored at baseline and during treatment. Potassium supplementation may need to be held during antibiotic therapy, especially when other predisposing factors for hyperkalemia are present. Peak potassium increase due to trimethoprim is delayed and generally occurs after 4 or more days of therapy.(3,5,6) When possible, alternative antibiotic therapy should be considered in patients with one or more risk factors for hyperkalemia, e.g. renal impairment, heart failure, age > 65 years, and/or receiving additional meds associated with hyperkalemia risk (e.g. ACE inhibitors, angiotensin II receptor blockers, aldosterone antagonists, NSAIDs).(6)

DISCUSSION: A nested case-control study evaluated the risk for hyperkalemia in 19,194 patients with newly diagnosed heart failure. Over a mean follow-up of 3.9 years 2,176 cases of hyperkalemia (96.7% with a potassium value of => 5.5 mmol/L) were identified. Study authors found that trimethoprim independently increased the risk for hyperkalemia (OR 2.82; 95% CI 1.88-4.23).(4) A retrospective cohort study evaluated the risk for hospitalization due to hyperkalemia in 393,039 elderly women (age >65 years) treated for a urinary tract infection (UTI) with trimethoprim-sulfamethoxazole (TMP-SMX) or another antibiotic (amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin). Baseline renal function was similar in all five antibiotic groups. When compared with amoxicillin, TMP-SMX use was associated with a 3.3-fold increased risk for hospitalization due to hyperkalemia. Ciprofloxacin, norfloxacin, and nitrofurantoin were not associated with a risk for hyperkalemia.(9) A prospective study of hospitalized patients evaluated the risk for hyperkalemia in patients who received standard dose TMP-SMX (<= 320 mg trimethoprim, <= 1600 mg sulfamethoxazole daily) versus a control group who received a different antibiotic for at least 5 days. The two groups were similar in age, renal function and use of potassium altering medications. Serum potassium concentration increased in TMP-SMX patients by 1.21 mmol/L (CI 1.09 - 1.32 mmol/L), a change which was statistically significant in patients with a pretreatment serum creatinine = or > 1.2. In control patients, serum potassium decreased during antibiotic therapy (change not quantitated by authors).(5)

Tryptophan/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use may result in additive effects on serotonin levels. MAOIs may potentiate the effects of tryptophan.(1)

CLINICAL EFFECTS: Concurrent administration of tryptophan with a MAO Inhibitor may result in serotonin syndrome and/or hypertensive crisis.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) In addition to these effects, disorientation, delirium, agitation, hypomania, shivering, ocular oscillation, and Babinski signs have been reported with concurrent tryptophan and phenelzine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving linezolid should not be administered tryptophan unless they can be closely monitored for serotonin syndrome. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a case report, a patient receiving metoclopramide and a TPN containing tryptophan developed serotonin syndrome following the addition of linezolid to therapy.(3) In a study in nine subjects, the administration of a single intravenous dose of tryptophan with tranylcypromine significantly increased the normal prolactin response to tryptophan. Four of the nine subjects developed a distinctive neuromotor syndrome characterized by hyperreflexia, ankle clonus, nystagmus, incoordination, tremor, myoclonic jerks, and nausea.(4) Another set of authors reported eight cases of delirium, ranging from mild to severe, in patients who received concurrent tranylcypromine and tryptophan. Symptoms developed within two days to 4 weeks of beginning concurrent therapy.(5) In a case report, the addition of tryptophan to a tranylcypromine regimen resulted in hypomania.(6) In another report, a patient developed hyperventilation, shivering, hyperthermia, increased muscle tone, and hyperreflexia when tryptophan was added to tranylcypromine therapy.(7) There are two reports of fatalities following the concurrent administration of tryptophan and tranylcypromine. In the first report, a a patient had been receiving chlorpromazine, lithium, and tryptophan when phenelzine was initiated. Four weeks later, the patient developed neuroleptic malignant syndrome and expired despite resuscitation efforts.(8) In the second report, a patient had been receiving fluoxetine, levothyroxine, propranolol, quinidine, and hydroxyzine. Fluoxetine was discontinued and tranylcypromine, thioridazine, and tryptophan were initiated. The patient developed neuroleptic malignant syndrome two and one-half hours after the first tryptophan dose and expired 24 hours later. (9) In a case report, the addition of tryptophan to a regimen that included phenelzine resulted in an acute behavioral and neurologic syndrome. The patient's symptoms resolved 24 hours after the discontinuation of both agents.(10) In another report, a patient developed hypomania following the addition of tryptophan to phenelzine therapy.(6) Another report describes the development of delirium following the addition of tryptophan to phenelzine.(11) One set of authors reported three cases of myoclonus, hyperreflexia, and diaphoresis following the addition of tryptophan to phenelzine therapy.(12) Some studies have shown that the addition of tryptophan to MAO Inhibitor therapy may have beneficial results, including greater improvement in depression and faster onset of effects.(13,14)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents That Increase Potassium/Baxdrostat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The combination of baxdrostat and agents that increase potassium such as aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements can have an additive effect on serum potassium levels.

CLINICAL EFFECTS: Concurrent use of baxdrostat and agents that increase potassium may result in hyperkalemia, which may be severe.

PREDISPOSING FACTORS: More frequent monitoring is recommended for patients at increased risk of hyperkalemia (e.g., patients greater than or equal to 65 years or age, those with diabetes mellitus or chronic kidney disease).(1)

PATIENT MANAGEMENT: The manufacturer of baxdrostat states concurrent use with medications that may increase potassium warrants more frequent monitoring of serum potassium.(1) Assess serum potassium prior to initiation of baxdrostat and monitor periodically during treatment. Correct serum potassium abnormalities prior to initiation of baxdrostat.(1) If hyperkalemia occurs, treat hyperkalemia and consider interrupting or discontinuing baxdrostat. Consider more frequent monitoring of serum potassium in patients who restart baxdrostat after experiencing hyperkalemia. Permanently discontinue baxdrostat if clinically significant hyperkalemia recurs.(1)

DISCUSSION: Baxdrostat may increase potassium. Concurrent use with aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements may have additive effects on serum potassium levels, resulting in hyperkalemia. The risk of hyperkalemia can be reduced by monitoring serum potassium more frequently when baxdrostat is administered concomitantly with these agents.

Magnesium Salts, Injectable/Nondepolarizing Muscle Relaxants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Magnesium may reduce postjunctional membrane neuromuscular blocking action of nondepolarizing muscle relaxants. Parenterally administered magnesium may potentiate the effects of the nondepolarizing muscle relaxants.

CLINICAL EFFECTS: Increased neuromuscular blockade with profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor respiratory function when parenteral magnesium and nondepolarizing muscle relaxants are administered concurrently. Adjust the dose of the neuromuscular blocking agent accordingly. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: The effects of nondepolarizing muscle relaxants have been reported to be increased in laboratory animals and in humans by concomitant administration of magnesium sulfate. Respiratory depression has been reported.

Potassium Supplements/Aliskiren

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aliskiren may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with aliskiren may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and aliskiren.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. Increased potassium levels have also been seen with aliskiren. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with aliskiren.

Potassium Supplements/Angiotensin Ii Receptor Blocker (ARB)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with ARBs may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ARBs.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ARB therapy is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ARBs.

Potassium Supplements/Drospirenone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. Potassium supplements also increase potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of drospirenone and potassium supplements may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, heparin, and NSAIDs may increase potassium levels.(1)

PATIENT MANAGEMENT: Patients receiving drospirenone with a potassium supplement should have their serum potassium level checked during the first treatment cycle.(1)

DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of potassium-supplements also increase potassium levels.(1)

Potassium Supplements/Selected Ace Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium.

CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors may result in hyperkalemia. CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors may result in hyperkalemia.

PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus.

PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ACE inhibitors. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ACE inhibitors.

DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ACE inhibitors. Selected ACE inhibitors linked to this monograph include: alacepril, cilazapril, delapril, imidapril, perindopril, spirapril, temocapril, and zofenopril. DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ACE inhibitors. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril.

Serotonergic Agents/Centanafadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Serotonergic Agents/Gepirone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gepirone is a serotonin receptor agonist. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents may increase the risk of hypertensive crisis and serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1)

Serotonergic Agents/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1)

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6)

There is no enhanced messaging for this drug.

• Digitalis toxicity
• Familial hyperkalemic periodic paralysis
• Hypercalcemia
• Hyperchloremia
• Hyperkalemia
• Phenylketonuria

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Complete atrioventricular block
• Hypercalcinuria
• Hyporeninemic hypoaldosteronism
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myotonia congenita - autosomal dominant form
• Severe burns

• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Sarcoidosis

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.