Usual dose

Determination of dose should be based on severity of pain and patient response.

Pediatric dose

1 mg/kg/dose; see Maternal/Child.

Dose adjustments

Reduced dose may be required in the elderly or debilitated, in hepatic or renal disease, or in numerous other disease entities; see Precautions. ■ Doses appropriate for the general population may cause serious respiratory depression in vulnerable patients. ■ Increase doses as required if analgesia is inadequate, tolerance develops, or pain severity increases. The first sign of tolerance is usually a reduced duration of effect. ■ Decrease dose by 25% to 50% when administered concomitantly with phenothiazines and other centrally acting medications (e.g., sedatives). ■ See Drug/Lab Interactions.

Dilution

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

Actions

A synthetic narcotic analgesic and descending CNS depressant, similar to morphine. Has multiple actions; the most prominent involve the CNS and organs composed of smooth muscle. Principal actions of therapeutic value are analgesia and sedation. May produce less smooth muscle spasm, constipation, and depression of the cough reflex than equianalgesic doses of morphine. A parenteral dose of meperidine 60 to 80 mg is approximately equivalent in analgesic effect to 10 mg of morphine. Onset of action occurs in about 5 minutes and lasts for about 2 to 4 hours. Readily absorbed and distributed throughout the body. Metabolized to an active, toxic metabolite (normeperidine) in the liver, its extended half-life (15 to 30 hours) may lead to cumulative effects. Excreted in the urine. Crosses the placental barrier. Secreted in breast milk.

Indications and uses

Short-term relief of moderate to severe pain. ■ Preoperative medication. ■ Support of anesthesia. ■ Obstetric analgesia.

Contraindications

Hypersensitivity to meperidine, patients who have received MAO inhibitors (e.g., selegiline [Eldepryl]) in the previous 14 days.

Precautions

Use of meperidine as a first-line analgesic for pain is discouraged due to its short duration of action and the risk of accumulation of its toxic metabolite, normeperidine. Accumulation of normeperidine may increase the risk of toxicity (e.g., seizures). If its use in acute pain (in patients without renal or CNS disease) cannot be avoided, the American Pain Society and ISMP recommend limiting treatment to 48 hours or less and not exceeding 600 mg/24 hr. ■ Use with caution in glaucoma, head injuries, increased intracranial pressure (elevates spinal fluid pressure), asthma, chronic obstructive pulmonary disease, decreased respiratory reserve or respiratory depression, supraventricular tachycardia, convulsions, acute abdominal conditions before diagnosis, the elderly and debilitated, and hepatic or renal insufficiency. ■ Use with caution and in reduced doses in patients receiving concurrent therapy with other narcotic analgesics, general anesthetics, phenothiazines (e.g., promethazine [Phenergan], prochlorperazine [Compazine]), sedative-hypnotics (including barbiturates [e.g., phenobarbital]), tricyclic antidepressants (e.g., imipramine [Tofranil]), and other CNS depressants, including alcohol. Use may result in respiratory depression, hypotension, and profound sedation or coma. See Drug/Lab Interactions. ■ Use with caution in patients with renal dysfunction; normeperidine may accumulate, resulting in increased CNS toxicity. ■ May cause severe hypotension in postoperative patients or in any patient whose ability to maintain blood pressure has been compromised by depleted blood volume or concomitant administration of drugs that can cause hypotension (e.g., anesthetics, phenothiazines). ■ Use with caution in patients with sickle cell anemia, hypothyroidism, Addison’s disease, pheochromocytoma, and prostatic hypertrophy or urethral stricture. Reduced doses may be indicated; see Dose Adjustments. ■ Cough reflex may be suppressed. ■ Morphine is usually preferred for pain during an acute MI. ■ IM route frequently used. Frequent IM injections may lead to severe fibrosis of muscle tissue. ■ Do not use in patients for any long-term pain relief (e.g., cancer). ■ Psychological and physical dependence and tolerance may develop with repeated administration.

Drug/lab interactions

Potentiated by acyclovir (Zovirax), anticholinergics, cimetidine (Tagamet), tricyclic antidepressants (e.g., imipramine [Tofranil]), isoniazid (INH), neostigmine, neuromuscular blocking agents (e.g., atracurium [Tracrium]), phenothiazines, general anesthetics, other narcotic analgesics, and CNS depressants including alcohol. Side effects (e.g., CNS depression, constipation, hypotension) may be additive. Reduced dosage of both drugs may be indicated. ■ Do not use with MAO inhibitors (e.g., selegiline [Eldepryl]); may cause cardiovascular collapse. ■ Avoid concurrent use with sibutramine (Meridia); may precipitate serotonin syndrome (e.g., altered consciousness, CNS irritability, motor weakness, myoclonus, shivering). ■ Mixed agonists/antagonists (e.g., pentazocine [Talwin], nalbuphine, butorphanol [Stadol]) may decrease analgesic effect of meperidine and/or precipitate withdrawal symptoms. ■ Concurrent use with protease inhibitors (e.g., saquinavir [Invirase], ritonavir [Norvir]) not recommended. May increase meperidine serum concentrations and increase the risk of side effects, including seizures and cardiac arrhythmias. ■ Hydantoins (e.g., phenytoin [Dilantin]) may increase metabolism and decrease the half-life of meperidine; however, increased normeperidine levels have been seen. ■ Metabolism increased and analgesic effects may be decreased or delayed in smokers.

Side effects

Dizziness, flushing, light-headedness, nausea, postural hypotension, rash, restlessness, sedation, sweating, syncope, vomiting. Side effects associated with histamine release, convulsions, and constipation may be more common with meperidine than with most other narcotic analgesics.

Antidote

With increasing severity of minor side effects or onset of any major side effect, discontinue the drug and notify the physician. A patent airway, artificial respiration, oxygen therapy, and other symptomatic treatment must be instituted promptly. Naloxone hydrochloride will reverse cardiovascular, CNS, and respiratory reactions. In patients who are physically dependent on narcotics, either avoid the use of a narcotic antagonist or use extreme caution and doses as small as one-fifth to one-tenth of the usual initial dose to avoid precipitating an acute withdrawal syndrome. In all patients, adjust and titrate the dose of a narcotic antagonist to reverse side effects without reversing pain control. Avoid total reversal of pain control. Resuscitate as necessary.

Usual dose

Dose ranges from 500 mg to 2 Gm and depends on type and severity of infection.

Pediatric dose

30 to 120 mg/kg/day divided (10 to 40 mg) every 8 hours depending on type and severity of infection. Maximum dose is 6 Gm/day. See Maternal/Child.

Dose adjustments

Reduced dose required if CrCl is less than 51 mL/min based on the following chart.

Consult package insert or front matter of this text for formula to convert SCr to CrCl. ■ No dose adjustment necessary in impaired hepatic function. ■ Reduced dose may be required in the elderly based on decreased renal function. ■ Information is inadequate for use in patients on hemodialysis or peritoneal dialysis. ■ No experience in pediatric patients with renal impairment.

Dilution

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

Manufacturer states, “Meropenem should not be mixed or physically added to solutions containing other drugs; compatibility not established.”

One source suggests the following compatibilities:

Rate of administration

Actions

A synthetic, broad-spectrum, carbapenem antibiotic. Bactericidal to selected gramnegative, gram-positive, and anaerobic organisms. Bactericidal activity results from the inhibition of cell wall synthesis. Readily penetrates the cell wall of susceptible organisms to reach penicillin-binding protein targets. Has significant stability to hydrolysis by penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria. Peak plasma concentrations reached by the end of an infusion. Penetrates well into most body fluids and tissues, including cerebrospinal fluid. Peak fluid and tissue concentrations reached in 0.5 to 1.5 hours. Minimal protein binding. Elimination half-life averages 1 hour in adults, 1.5 hours in pediatric patients age 3 months to 2 years, and 2.7 hours in infants under 3 months of age. 70% recovered as unchanged drug in urine within 12 hours. Not yet known if it crosses the placental barrier. Secreted in breast milk.

Indications and uses

Indicated as single-agent therapy for treatment of the specific infections caused by susceptible organisms. Is useful as presumptive therapy in the indicated infections before identification of the causative organism because of its broad spectrum of activity. Treatment of intra-abdominal infections (e.g., complicated appendicitis, peritonitis) in adults and pediatric patients. ■ Treatment of complicated skin and skin structure infections in adults and pediatric patients 3 months of age and older. ■ Treatment of bacterial meningitis in pediatric patients 3 months of age and older. Efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin-nonsusceptible isolates of Streptococcus pneumoniae has not been established. Meropenem has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

Contraindications

History of hypersensitivity to meropenem, its components, any other carbapenem antibiotic (e.g., imipenem-cilastatin [Primaxin]), or patients with demonstrated anaphylaxis to beta-lactams; see Precautions.

Precautions

Specific sensitivity studies are indicated to determine susceptibility of the causative organism to meropenem. ■ To reduce the development of drug-resistant bacteria and maintain its effectiveness, meropenem should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria. ■ Serious and occasionally fatal hypersensitivity reactions have been reported in patients receiving therapy with beta-lactams (e.g., penicillins, cephalosporins, carbapenems). More likely in patients with a history of sensitivity to multiple allergens; obtain a careful history. Crosssensitivity is possible. ■ Seizures and other adverse CNS reactions have been reported. Occurred most commonly in patients with a history of CNS disorders (e.g., brain lesions, history of seizures) or with bacterial meningitis and/or compromised renal function. Use extreme caution; continue administration of anticonvulsants in patients with known seizure disorders. ■ Use with caution in patients with impaired renal function; thrombocytopenia may occur and the incidence of heart failure, kidney failure, seizures, and shock may be increased; see Dose Adjustments. ■ May have cross-resistance with strains resistant to other carbapenems (e.g., imipenem-cilastatin [Primaxin]). ■ Localized clusters of infections resulting from carbapenem-resistant bacteria have been reported in some regions. ■ Has the potential for neuromotor impairment (e.g., headaches, paresthesias, seizures) that can interfere with mental alertness and/or cause motor impairment; see Patient Education. ■ Avoid prolonged use of drug; superinfection caused by overgrowth of nonsusceptible organisms may result. ■ Clostridium difficile–associated diarrhea (CDAD) has been reported. May range from mild diarrhea to fatal colitis. Consider in patients who present with diarrhea during or after treatment with meropenem. ■ See Drug/Lab Interactions.

Drug/lab interactions

Carbapenems may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in a loss of seizure control. Monitor valproic acid levels. Consider alternative antibacterial therapy. If administration of meropenem is necessary, supplemental anticonvulsant therapy should be considered. ■ Probenecid inhibits renal excretion and increases serum levels of meropenem, extending its half-life and increasing systemic exposure; coadministration is not recommended. ■ May be synergistic with aminoglycosides against some isolates of Pseudomonas aeruginosa.

Side effects

Toxicity rate is usually low.

Antidote

Notify physician of all side effects. Most treated symptomatically. Discontinue immediately if a hypersensitivity reaction occurs. Treat hypersensitivity reactions as indicated; may require epinephrine, airway management, oxygen, IV fluids, antihistamines (e.g., diphenhydramine [Benadryl]), corticosteroids (e.g., hydrocortisone sodium succinate [Solu-Cortef]), and pressor amines (e.g., dopamine). If focal tremors, myoclonus, or seizures occur, evaluate neurologically, initiate anticonvulsant therapy, and decide whether to decrease or discontinue meropenem. Mild cases of CDAD may respond to discontinuation of meropenem. Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. Readily removed by hemodialysis.

Usual dose

Specific testing recommended before each dose of ifosfamide; see Monitor.

Dose adjustments

Dose of mesna must be repeated each day ifosfamide is administered and adjusted with each increase or decrease of the ifosfamide dose.

Dilution

Each 100 mg (1 mL) must be diluted in a minimum of 4 mL D5W, D5NS, D5/¹/₄NS, D5/¹/₃NS, D5/¹/₂NS, NS, or LR. Desired concentration is 20 mg/mL.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

A single dose over a minimum of 1 minute given as a single agent. Administer at rate for ifosfamide if given together. Another source recommends administering as an infusion over 15 to 30 minutes or as a continuous infusion maintained for 12 to 24 hours after completion of the ifosfamide infusion.

Actions

A detoxifying agent. Reacts chemically in the kidney with urotoxic ifosfamide metabolites to detoxify them and inhibit hemorrhagic cystitis. Remains in the intravascular compartment and much of a single dose is excreted within 4 hours in urine. Does not appear to interfere with the antitumor efficacy of ifosfamide.

Indications and uses

A prophylactic agent used to reduce the incidence of hemorrhagic cystitis caused by ifosfamide.

Contraindications

Hypersensitivity to mesna or other thiol compounds.

Precautions

Repeated doses are required to maintain adequate levels of mesna in the kidneys and bladder to detoxify urotoxic ifosfamide metabolites. ■ Hemorrhagic cystitis caused by ifosfamide is dose dependent. Mesna is most effective when ifosfamide dose is less than 1.2 Gm/M²/24 hr. Somewhat less effective when ifosfamide dose is 2 to 4 Gm/M²/24 hr. If hematuria develops with appropriate doses of mesna, ifosfamide dose may need to be reduced or discontinued. ■ Does not inhibit any other side effects or toxicities caused by ifosfamide therapy. ■ Not effective in preventing hematuria caused by other conditions (e.g., thrombocytopenia). ■ Hypersensitivity reactions ranging from mild to anaphylaxis have been reported. Patients with autoimmune disorders who are treated with cyclophosphamide and mesna may have a higher incidence of hypersensitivity reactions.

Drug/lab interactions

May cause a false-positive reaction for urinary ketones. If a red-violet color develops, glacial acetic acid returns the coloring to violet.

Side effects

Antidote

No specific antidote. Keep physician informed of all side effects. Notify promptly if signs of overdose occur. Resuscitate as necessary.

Usual dose

Parenteral administration permitted only under specific conditions; see Indications and Precautions.

Dosing is complex and requires extensive individualization. Extended half-life, potential for prolonged respiratory depressant effects, retention in the liver (prolonging the potential duration of action), and high interpatient variability in absorption, metabolism, and relative analgesic potency must be considered.

Dose adjustments

Lower-end initial doses are indicated in the elderly; consider impaired organ function and concomitant disease or drug therapy. ■ Reduced initial doses are indicated in debilitated patients and in those with severe impaired hepatic or renal function. ■ Clearance may be increased and half-life decreased during pregnancy. Increased doses or shorter intervals between doses may be indicated; see Maternal/Child.

Dilution

May be given undiluted; however, to facilitate titration, further dilution of each mL with 1 to 5 mL of NS is appropriate. May be given through Y-tube or three-way stopcock of infusion set.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

A single dose as an injection over a minimum of several minutes. Titrate according to symptom relief and respiratory rate; side effects may be increased if rate of injection is too rapid.

Actions

A synthetic opioid analgesic with actions similar to those of morphine. Duration of analgesic action is from 4 to 8 hours. Respiratory depressant effects occur later and persist longer than its peak analgesic effects. With repeated dosing, methadone may be retained in the liver and then slowly released, thereby prolonging the duration of action while plasma concentrations are low. Highly protein bound (85% to 90%). Metabolized in the liver by various enzymes (including cytochrome P₄₅₀ enzymes) to inactive metabolites. Half-life is prolonged (ranges from 8 to 59 hours). Eliminated by extensive biotransformation followed by renal and fecal elimination. Secreted in saliva, breast milk, amniotic fluid, and umbilical cord plasma.

Indications and uses

Treatment of moderate to severe pain not responsive to nonnarcotic analgesics. ■ Temporary treatment in opioid-dependent patients unable to take oral medication. ■ Used PO for detoxification or maintenance in opioid addiction. ■ Parenteral products are not approved for outpatient use.

Contraindications

Known hypersensitivity to methadone or any of its components. ■ Any situation in which opioids are contraindicated (e.g., patients with respiratory depression [where resuscitative equipment is not readily available or in unmonitored settings], patients with acute bronchial asthma or hypercarbia). ■ Other sources add paralytic ileus and concurrent use of selegiline (Zelapar, Eldepryl).

Precautions

If the parenteral route is indicated, the IV route is preferred; absorption by the IM or SC routes is unpredictable and may cause local tissue reaction. ■ Schedule II opioid agonists, including hydromorphone, morphine, oxymorphone, oxycodone, fentanyl, and methadone, have the highest potential for abuse and risk of producing respiratory depression. Alcohol, CNS depressants, and other opioids potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death; see Drug/Lab Interactions. ■ Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists. Close monitoring is required during these times as well as during dose titration. ■ The peak respiratory depressant effects of methadone usually occur later and last longer than the peak analgesic effects. Iatrogenic overdose may occur with short-term use, particularly during treatment initiation and dose titration. ■ Patients tolerant to other opioids may still be sensitive to methadone. This incomplete cross-tolerance makes dose selection difficult when converting to methadone. Deaths have been reported. A high degree of “opioid tolerance” does not eliminate the possibility of methadone toxicity. ■ Prolongation of the QT interval and infrequent cases of arrhythmia (including torsades de pointes) have been reported. May occur with any dose but appears to be more common with higher dose treatment (greater than 200 mg/day). ■ Use with caution in patients at risk for development of prolonged QT interval (e.g., cardiac conduction abnormalities, cardiac hypertrophy, hypokalemia, hypomagnesemia) and in patients receiving concurrent treatment with other drugs that may induce electrolyte disturbances (e.g., diuretics, laxatives and, rarely, mineralocorticoid hormones) or other drugs that may prolong the QT interval; see Drug/Lab Interactions. ■ Initiate treatment for analgesic therapy in patients with acute or chronic pain only if benefits outweigh the increased risk of QT prolongation with high doses. ■ Use extreme caution in patients with potential respiratory insufficiency (e.g., elderly or debilitated patients, conditions accompanied by hypoxia or hypercapnia or decreased respiratory reserve [e.g., asthma, COPD, pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma]). Usual doses may decrease respiratory drive and simultaneously increase airway resistance, resulting in apnea. Consider use of non-opioid analgesics. If methadone is required, administer at lowest effective dose under close medical supervision. ■ Use caution in elderly or debilitated patients, severe impaired hepatic or renal function, Addison’s disease, hypothyroidism, prostatic hypertrophy, or urethral stricture; see Dose Adjustments. ■ Use with caution in patients with head injury, other intracranial lesions, or pre-existing increased intracranial pressure. Cerebrospinal fluid pressure may be markedly exaggerated, and the clinical course of head injuries may be obscured. ■ May mask symptoms and make diagnosis of acute abdominal conditions difficult. ■ May cause severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). ■ Patients with impaired hepatic function may be at increased risk of accumulating methadone after multiple dosing. ■ Because of their opioid tolerance, patients receiving maintenance doses may require increased or more frequent doses of opioids to treat physical trauma, postoperative pain, or other acute pain. ■ Do not increase methadone dose for symptoms of anxiety. ■ Abrupt discontinuation of methadone is not recommended; may result in withdrawal symptoms (e.g., chills, lacrimation, myalgia, mydriasis, perspiration, restlessness, rhinorrhea, yawning) and may lead to relapse of illicit drug use.

Drug/lab interactions

May have additive effects with other CNS depressants (e.g., alcohol, general anesthetics, hypnotics or sedatives [e.g., benzodiazepines (e.g., diazepam [Valium], midazolam [Versed]), barbiturates [e.g., phenobarbital (Luminal)], other opioid analgesics, phenothiazines [e.g., prochlorperazine (Compazine)]). Concurrent use may result in hypotension, profound sedation, respiratory depression, coma, or death. ■ Not recommended for concurrent administration with opioid antagonists (e.g., naloxone, naltrexone [ReVia]), mixed agonist/antagonists, or partial agonists (e.g., buprenorphine [Buprenex], butorphanol [Stadol], nalbuphine, pentazocine [Talwin]); may precipitate withdrawal symptoms and/or reduce analgesic effect in patients maintained on methadone. ■ Metabolism increased and serum concentrations decreased by cytochrome P₄₅₀ inducers (e.g., carbamazepine [Tegretol], phenobarbital [Luminal], phenytoin [Dilantin], rifampin [Rifadin], St. John’s wort), efavirenz (Sustiva), nevirapine (Viramune), ritonavir (Norvir), and ritonavir/lopinavir combination (Kaletra). With concurrent administration, the effects of methadone are decreased; monitor for S/S of withdrawal, and adjust methadone dose as indicated. ■ Metabolism decreased and serum concentrations increased by cytochrome P₄₅₀ inhibitors (e.g., azole antifungal agents [e.g., itraconazole (Sporanox), ketoconazole (Nizoral)], macrolide antibiotics [e.g., erythromycin], selective serotonin reuptake inhibitors (SSRIs) [e.g., fluvoxamine (Luvox), sertraline (Zoloft)]). With concurrent administration, monitor methadone serum concentrations to prevent methadone toxicity. ■ May increase serum levels of desipramine (Norpramin). ■ May increase AUC of zidovudine and result in zidovudine toxicity. ■ May decrease AUC and peak levels of didanosine (Videx) and stavudine (Zerit). ■ Use caution with MAO inhibitors (e.g., selegiline [Eldepryl]) administered within 14 days and test for sensitivity. MAO inhibitors have caused cardiovascular collapse with other opioids (e.g., meperidine [Demerol]), not reported with methadone; see Contraindications. ■ Use extreme caution with other drugs that prolong the QT interval (e.g., Class Ia antiarrhythmic agents [e.g., quinidine, procainamide (Pronestyl)], Class III antiarrhythmic agents [e.g., amiodarone (Nexterone), sotalol (Betapace)], calcium channel blockers [e.g., diltiazem (Cardizem), verapamil], some neuroleptics [e.g., phenothiazines (e.g., chlorpromazine [Thorazine])], and tricyclic antidepressants [e.g., amitriptyline (Elavil), imipramine (Tofranil)]).

Side effects

Hypotension and respiratory depression are dose limiting. Respiratory arrest, shock, cardiac arrest, and death have occurred.

Dizziness, light-headedness, nausea and vomiting, sedation, and sweating occur most frequently. Other reported side effects include abdominal pain, agitation, anorexia, antidiuretic effect, arrhythmias, asthenia, biliary tract spasm, cardiomyopathy, confusion, constipation, chronic hepatitis, dry mouth, edema, euphoria, flushing, glossitis, headache, heart failure, hypokalemia, hypomagnesemia, hypotension, palpitations, phlebitis, prolonged QT interval, pulmonary edema, pruritus, seizures, skin rashes, syncope, thrombocytopenia (reversible), torsades de pointes, urinary retention or hesitancy, urticaria, visual disturbances.

Antidote

Keep physician informed of all side effects; may be treated symptomatically. During prolonged administration (patients on maintenance), side effects usually decrease with time. Lower doses of methadone may be indicated for dizziness, light-headedness, nausea and vomiting, sedation, and sweating. Management of major side effects or overdose requires establishing a patent airway, instituting assisted or controlled ventilation, IV fluids, vasopressors, and other supportive measures as indicated. Do not administer opioid antagonists to physically dependent patients unless clinically significant respiratory or cardiovascular depression occurs. May precipitate an acute withdrawal syndrome. If a decision is made to treat serious respiratory or circulatory depression in a physically dependent patient, administration of the antagonist should begin with care and by titration with smaller than usual doses of the antagonist. Opioid antagonists (e.g., naloxone)have a much shorter duration of action than methadone and may need repeating for up to 48 hours. Continuous monitoring is required. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion may not be useful to increase methadone or metabolite elimination; however, urine acidification has been shown to increase renal elimination of methadone.

Usual dose

Many dose limitations based on patient condition, renal and hepatic function, and concomitant drugs or therapies; see Precautions/Monitor. Doses between 100 and 500 mg/M² may require leucovorin calcium rescue. Doses over 500 mg/M² require leucovorin calcium rescue; see leucovorin calcium or levoleucovorin (Fusilev) monograph. Part of numerous protocols that change as new advances in antileukemic therapy and other cancers are developed. Selections from those protocols are included in the following text.

Pediatric dose

Safety for use in pediatric patients is limited to chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. May contain benzyl alcohol; not recommended for use in neonates. See Maternal/Child.

Dose adjustments

Manufacturer does not provide information on dose adjustment in patients with impaired renal or hepatic function. However, various recommendations are available in the literature. In patients with impaired hepatic function, one source recommends administering 75% of dose if bilirubin is between 3.1 and 5 or if transaminases are greater than 3 times the ULN; if bilirubin above 5, omit dose. ■ Reduced doses may be required in patients with impaired renal function. Suggested guidelines are to administer 50% of a dose with a CrCl of 10 to 50 mL/min, and avoid use with a CrCl of less than 10 mL/min in adult patients. In pediatric patients, administer 50% of a dose with a CrCl of 10 to 50 mL/min and 30% of a dose with a CrCl of less than 10 mL/min/1.73M². ■ Reduced dose may be required in patients with ascites or pleural effusions, in the very young or very elderly, in the debilitated, and in other diseases; see Precautions. ■ Often used with other antineoplastic drugs to achieve tumor remission. ■ See Drug/Lab Interactions.

Dilution

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

Actions

An antimetabolite and folic acid antagonist. Inhibits dihydrofolic acid reductase. Cell cycle–specific for the S phase. It interferes with DNA synthesis, repair, and cellular replication. Rapidly proliferating tissues are more sensitive to this effect. Widely distributed and is approximately 50% protein bound. Undergoes some hepatic and intracellular metabolism. Half-life is dose dependent and is 3 to 10 hours in patients receiving low-dose antineoplastic therapy and 8 to 15 hours in patients receiving high-dose methotrexate therapy. 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. Clearance rates decrease with higher doses. Does not cross blood-brain barrier. Secreted in breast milk.

Indications and uses

Used for life-threatening neoplastic disease alone or in combination with other anticancer agents in the treatment of acute lymphocytic leukemia, breast cancer, epidermal tumors of the head and neck, small-cell and squamous cell lung cancer, non-Hodgkin’s lymphoma, advanced mycosis fungoides (cutaneous T-cell lymphoma). ■ Severe disabling psoriasis or rheumatoid arthritis unresponsive to other treatment. Diagnosis of psoriasis should be established by biopsy and/or dermatology consultation before use. ■ To prolong relapse-free survival in patients with nonmetastatic osteosarcoma who have undergone surgical resection or amputation of the primary tumor. Given as a high-dose regimen with leucovorin rescue in combination with other chemotherapeutic agents. ■ Given PO or IM for early-stage mycosis fungoides, trophoblastic diseases (gestation choriocarcinoma, chorioadenoma destruens, and hydatidiform mole), polyarticular-course juvenile rheumatoid arthritis, rheumatoid arthritis, and other diagnoses, and given intrathecally for treatment and prophylaxis of meningeal leukemia.

Contraindications

Hypersensitivity to methotrexate; breast-feeding mothers. Contraindicated in pregnant females with psoriasis or rheumatoid arthritis and should be used during pregnancy for treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Contraindicated in psoriasis or rheumatoid arthritis patients with immunodeficiency syndromes, pre-existing blood dyscrasias, or chronic liver disease.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist. ■ Methotrexate should be used only in life-threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not responsive to other forms of therapy. ■ Deaths have been reported with methotrexate use in the treatment of malignancy, psoriasis, and rheumatoid arthritis. ■ Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Careful monitoring, dose reduction and, in some cases, discontinuation of therapy are required; consider evacuating excess fluid from ascites and pleural effusions before treatment if possible. ■ Methotrexate can suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. ■ Serious and sometimes fatal bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant use of methotrexate (usually high doses) and some NSAIDs; see Drug/Lab Interactions. ■ Leukoencephalopathy has been reported in patients who have received both IV methotrexate and craniospinal irradiation. ■ A transient stroke-like encephalopathy has been reported with high-dose methotrexate therapy. Symptoms may include confusion, hemiparesis, transient blindness, seizures, and coma. ■ Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, may occur at any time, may occur even with low doses, and has been fatal. Patients may present with fever, dry cough, dyspnea, hypoxemia, and an infiltrate on chest x-ray. May require interruption of therapy and is not always fully reversible. ■ Severe skin reactions can occur at any time and have been fatal. ■ Transient elevations in liver enzymes may occur early during treatment. Chronic hepatotoxicity (fibrosis and cirrhosis) occurs more frequently with prolonged use and a total dose of at least 1.5 Gm. Persistent abnormalities in liver function tests and/or depression of serum albumin may be indicators of serious liver toxicity. Has resulted in deaths; see Monitor. ■ Use with extreme caution in patients with ascites, bone marrow suppression, folate deficiency, GI obstruction, impaired renal or liver function, infection, peptic ulcer, pleural effusion, or ulcerative colitis; in debilitated patients; and in the very young or very elderly. ■ Diarrhea and ulcerative stomatitis will require interrupting therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur. ■ Tumor lysis syndrome may occur, and S/S include hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, urate crystalluria, and renal failure. Prevent or alleviate tumor lysis syndrome with appropriate supportive and pharmacologic measures; see Monitor. ■ Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur. ■ Risk of soft tissue necrosis and osteonecrosis may be increased with concomitant use of methotrexate and radiotherapy. ■ May cause renal damage that may lead to acute renal failure. Nonreversible oliguric renal failure is likely to develop in patients who experience delayed early methotrexate elimination. ■ Malignant lymphomas have been reported. May occur in patients receiving low-dose methotrexate and may not require cytotoxic treatment; discontinue methotrexate first and initiate appropriate treatment if the lymphoma does not regress. ■ Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors; see Drug Interactions.

Drug/lab interactions

The following drugs may enhance methotrexate toxicity when administered concomitantly: cyclosporine (Sandimmune), any hepatotoxic drug (e.g., azathioprine, retinoids [vitamin A], sulfasalazine [Azulfidine]), etretinate (Tegison), NSAIDs (e.g., ibuprofen [Advil, Motrin], ketoprofen, naproxen [Aleve, Naprosyn]), penicillins (e.g., amoxicillin, nafcillin [Nallpen]), probenecid, salicylates, sulfonamides, phenytoin (Dilantin), pyrimethamine, trimethoprim (component of sulfamethoxazole/trimethoprim), and vancomycin (given up to 10 days prior to methotrexate); interactions may be life threatening. Monitoring serum levels and/or reduced doses of methotrexate may be indicated or a longer duration of leucovorin calcium rescue may be required. One source suggests delaying administration of aspirin, NSAIDs, and probenecid for 48 hours after larger doses of methotrexate; see Precautions. ■ NSAIDs are used in the treatment of rheumatoid arthritis in combination with low doses of methotrexate (e.g., 7.5 to 15 mg/week). Do not administer NSAIDs before or concomitantly with high doses of methotrexate (e.g., treatment of osteosarcoma); deaths from severe hematologic and GI toxicity have been reported. ■ Use caution if high-dose methotrexate is administered in combination with nephrotoxic chemotherapy agents (e.g., cisplatin). ■ Concurrent use of methotrexate (primarily at high dose) with some proton pump inhibitors such as esomeprazole (Nexium), omeprazole (Prilosec), and pantoprazole (Protonix) may cause prolonged elevation of serum levels of methotrexate and its metabolite, hydroxymethotrexate, leading to toxicity. Discontinue several days before methotrexate administration. Consider an H₂ antagonist (e.g., ranitidine [Zantac]). ■ Doxycycline may increase toxicity of methotrexate in high-dose regimens. ■ Vitamins with folic acid may inhibit the antifolate effects of methotrexate, decreasing effectiveness. ■ May increase serum levels of mercaptopurine (Purinethol); dose adjustment may be required. ■ Do not administer live virus vaccines to patients receiving antineoplastic drugs. ■ Procarbazine (Matulane) may increase nephrotoxicity of methotrexate. Allow 72 hours between last dose of procarbazine and first dose of methotrexate. ■ Monitor for signs of increased bone marrow suppression with sulfonamides (e.g., sulfisoxazole [Gantrisin], SMZ-TMP [Bactrim]), bone marrow–suppressing agents (e.g., antineoplastics), and radiation therapy. May also cause SMZ-TMP (Bactrim)-induced megaloblastic anemia. ■ May decrease theophylline clearance and increase serum levels; monitor theophylline serum levels with concurrent use. ■ Urinary alkalinizers increase renal excretion and may reduce effectiveness.

Side effects

Toxicity usually dose related. Death can occur from average doses, high doses, drug interactions (e.g., NSAIDs), bone marrow toxicity, GI toxicity, hepatic toxicity, pulmonary toxicity, and/or severe skin reactions. Abdominal distress, chills, decreased resistance to infection, dizziness, fatigue, fever, leukopenia, malaise, nausea, and ulcerative stomatitis occur most frequently. Other side effects reported include abortion (spontaneous), acne, acute hepatitis, agranulocytosis, alopecia, alveolitis, anaphylaxis, anemia, anorexia, aplastic anemia, azotemia, blurred vision, chronic fibrosis and cirrhosis, convulsions, COPD, cystitis, decreased serum albumin, defective oogenesis or spermatogenesis, diabetes, diarrhea, drowsiness, enteritis, eosinophilia, erythema multiforme, erythematous rashes, exfoliative dermatitis, fetal defects or death, furunculosis, GI ulceration and bleeding, gingivitis, gynecomastia, headache, hematemesis, hematuria, hemiparesis, hepatic failure, hepatotoxicity, hypotension, infertility, interstitial pneumonitis, liver enzyme elevations, lymphadenopathy and lymphoproliferative disorders, melena (passage of dark, tarry stools), menstrual dysfunction, nephropathy (severe), neutropenia, oligospermia (transient), opportunistic infections (e.g., cytomegalovirus infection, herpes zoster, histoplasmosis, Pneumocystis jiroveci pneumonia), pancreatitis, pancytopenia, paresis, pericardial effusion, pericarditis, pharyngitis, photosensitivity, pigmentary changes, proteinuria, pruritus, pseudomembranous colitis, renal failure, respiratory failure, respiratory fibrosis, skin necrosis, skin ulceration, speech impairment (aphasia, dysarthria), Stevens-Johnson syndrome, stomatitis, suppressed hematopoiesis (blood cell formation), telangiectasia, thrombocytopenia, thromboembolic events (e.g., arterial thrombosis, cerebral thrombosis, deep vein thrombosis, pulmonary embolus, retinal vein thrombosis, thrombophlebitis), toxic epidermal necrolysis, transient blindness, tumor lysis syndrome, urticaria, vaginal discharge, vomiting.

Antidote

Discontinue methotrexate and notify the physician of any side effects. Leucovorin calcium (citrovorum factor, folinic acid) may be given PO, IM, or IV promptly to counteract inadvertent overdose. Leucovorin calcium is also indicated as a planned rescue mechanism for large doses of methotrexate required to treat some malignancies. Doses equal to dose of methotrexate are frequently required. Should be given within 1 hour in overdose, 24 hours in rescue. See specific process for overdose and for rescue for high-dose MTX in leucovorin calcium monograph. Doses up to 150 mg or 100 mg/M² every 3 hours may be required if SCr is 50% or greater than baseline measurement before methotrexate administration. Serum methotrexate must come down to below 0.05 micromolar. Continuing hydration and urinary alkalinization are mandatory to prevent precipitation in renal tubules. Monitor fluid and electrolyte status until serum methotrexate has fallen to less than 0.05 micromolar and renal failure has resolved. Glucarpidase (Voraxaze), an antidote indicated for the treatment of toxic methotrexate concentration in patients with delayed methotrexate clearance due to impaired renal function, may also be used. If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase; see glucarpidase monograph. Administration of whole blood products (e.g., packed RBCs, platelets, leukocytes) and/or blood modifiers (e.g., darbepoetin alfa [Aranesp], epoetin alfa [Epogen], filgrastim [Neupogen, Zarxio], pegfilgrastim [Neulasta], sargramostim [Leukine]) may be indicated to treat bone marrow toxicity. Death may occur from the progression of most of these side effects. Symptomatic and supportive therapy is indicated. Charcoal hemoperfusion may be helpful, and/or acute intermittent hemodialysis with a high-flux dialyzer may be used to counteract toxicity or inadvertent overdose.

Usual dose

1 mL (0.2 mg); repeat doses should be IM or PO.

Dilution

Check expiration date on vial; methylergonovine deteriorates with age. May be given undiluted. Some clinicians recommend dilution with 5 mL of NS. Do not add to IV solutions. May be given through Y-tube or three-way stopcock of infusion set.

Compatibility

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

0.2 mg or fraction thereof over 1 minute. Too-rapid injection may cause severe nausea and vomiting. See Precautions.

Actions

A semi-synthetic ergot alkaloid used for prevention and control of postpartum hemorrhage. An oxytocic. It exerts a direct stimulation on the smooth muscle of the uterus. Increases tone, rate, and amplitude of rhythmic contractions. Shortens third-stage labor and reduces blood loss. In therapeutic doses the prolonged initial contraction of the uterus is followed by periods of relaxation and contraction. May also produce vasoconstriction, increase CVP and BP, and may rarely produce peripheral ischemia. Effective within minutes. Half-life approximately 3.4 hours. It is probably metabolized in the liver and excreted in feces. Secreted in breast milk.

Indications and uses

Routine management of uterine atony, hemorrhage, and subinvolution of the uterus following delivery of the placenta. ■ Control of uterine hemorrhage in the second stage of labor following delivery of the anterior shoulder.

Contraindications

Hypersensitivity, hypertension, pregnancy before third stage of labor (delivery of the placenta) except as stated in Indications, toxemia. ■ Contraindicated for concomitant use with potent CYP3A4 inhibitors (e.g., protease inhibitors [ritonavir (Norvir)], macrolide antibiotics [erythromycin], and azole antifungals [ketoconazole (Nizoral)]); see Drug/Lab Interactions.

Precautions

IV administration is for emergency use only. IM or oral routes are preferred and should be used after the initial IV dose. ■ IV use may induce hypertension and/or CVA. Give slowly and monitor BP. ■  Use caution in presence of sepsis, obliterative vascular disease, and hepatic or renal disease. ■ Patients with coronary artery disease or risk factors for coronary artery disease (e.g., diabetes, high cholesterol, obesity, smoking) may be more susceptible to developing myocardial ischemia and infarction associated with methylergonovine-induced vasospasm. ■ Use with caution during the second stage of labor. The necessity for manual removal of a retained placenta should occur rarely with proper technique and adequate allowance of time for a spontaneous separation. ■ Avoid intra-arterial or peri-arterial injection. ■ See Contraindications.

Drug/lab interactions

Severe hypertension and cerebrovascular accidents can result with ephedrine and other vasopressors. Hydralazine IV will reduce this hypertension. ■ Do not administer with potent CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin [Erythrocin], troleandomycin [TAO], clarithromycin [Biaxin]), HIV protease inhibitors (e.g., indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir]), reverse transcriptase inhibitors (e.g., delavirdine [Rescriptor]), or azole antifungals (e.g., ketoconazole [Nizoral], voriconazole [VFEND]). Serum levels increased. Elevated levels of ergot alkaloids can cause ergotism (i.e., risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities). ■ May be used cautiously with less potent CYP3A4 inhibitors (e.g., saquinavir [Invirase], nefazodone, fluconazole [Diflucan], grapefruit juice, fluoxetine [Prozac], fluvoxamine [Luvox], zileuton [Zyflo], and clotrimazole [Gyne-Lotrimin, Mycelex]). ■ Strong CYP3A4 inducers (e.g., rifampin [Rifadin], nevirapine [Viramune]) may decrease effectiveness of methylergonovine. ■ Anesthetics (e.g., halothane, methoxyflurane) may reduce oxytocic effect of methylergonovine. ■ Produces vasoconstriction and can be expected to reduce the effect of antianginal drugs (e.g., nitroglycerin). ■ Concomitant use with other ergot alkaloids or prostaglandins will produce additive effects. Use caution.

Side effects

Rare in therapeutic doses but may include the following:

Abdominal pain (caused by uterine contractions), bradycardia, chest pain (temporary), coronary artery spasm, diaphoresis, diarrhea, dilated pupils, dizziness, dyspnea, hallucinations, headache, hematuria, hypersensitivity reactions, hypertension (transient), hypotension, leg cramps, MI, nasal congestion, nausea, palpitations, rash, seizures, tachycardia, thrombophlebitis, tinnitus, vasoconstriction, vasospasm, vomiting, water intoxication, weakness.

Antidote

Discontinue the drug immediately at the onset of any side effect and notify the physician. Most side effects are transient unless there is severe toxicity and will be treated symptomatically. Use antiemetics (e.g., prochlorperazine [Compazine], ondansetron [Zofran]) for nausea and vomiting. Treat seizures with anticonvulsants (e.g., diazepam [Valium], phenytoin [Dilantin]). Maintain adequate pulmonary ventilation, especially if convulsions or coma develop. Correct hypotension with pressor drugs (e.g., dopamine). Apply warmth to extremities to control peripheral vasospasm.

Usual dose

Use the lowest possible dose to control the condition being treated. When reduction in dose is possible, the reduction should be gradual.

Average dose range is 10 to 40 mg initially. May be repeated every 4 to 6 hours as necessary. IV methylprednisolone is usually given in an emergency situation or when oral dosing is not feasible. Larger doses may be justified by patient condition. Repeat until adequate response, then decrease dose as indicated. Total dose usually does not exceed 1.5 Gm/24 hr, but higher doses have been used in life-threatening shock. High-dose treatment is used until patient condition stabilizes, usually no longer than 48 to 72 hours.

Pediatric dose

See Maternal/Child. Dose may be reduced for infants and pediatric patients but should be governed more by the severity of the condition and the response of the patient than by age or size. Dose should not be less than 0.5 mg/kg every 24 hours.

Dose adjustments

Reduced dose may be required; see Precautions and Drug/Lab Interactions. ■ Clearance of corticosteroids is decreased in patients with hypothyroidism and increased in patients with hyperthyroidism. Dose adjustment may be required.

Dilution

Available in Act-O-Vials containing 40 mg, 125 mg, 500 mg, and 1,000 mg. Each vial has an appropriate amount of diluent. Reconstitute by pressing down on the plastic activator, allowing the diluent into the lower chamber. Agitate gently. Remove the plastic tab covering the center of the stopper and sterilize the stopper with a suitable germicide. Using sterile technique, insert a needle through the center of the rubber stopper to withdraw diluted solution. To be diluted only with diluent supplied in Act-O-Vial. Also available in vials, including a 2,000-mg dose. Should be diluted with accompanying diluent or BWFI with benzyl alcohol. May be given as direct IV, as an infusion, or further diluted in desired amounts of D5W, D5NS, or NS.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

Manufacturer states, “Because of possible physical incompatibilities, should not be diluted or mixed with other solutions.”

One source suggests the following compatibilities:

Rate of administration

Actions

A glucocorticoid steroid with potent metabolic, anti-inflammatory actions and innumerable other effects. Has a greater anti-inflammatory potency than prednisolone and less tendency to cause excessive potassium and calcium excretion and sodium and water retention. Has five times the potency of hydrocortisone sodium succinate. Has minimal mineralocorticoid activity. Primarily used for anti-inflammatory and immunosuppressive effects. Demonstrable effects seen within 1 hour of administration. Primarily metabolized in the liver and excreted in the urine and feces. Dose almost completely excreted after 12 hours, which allows the use of very large doses with reasonable safety. Crosses the placental barrier. Secreted in breast milk.

Indications and uses

Includes treatment of allergic states, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematologic disorders, neoplastic diseases, nervous system disorders, ophthalmic diseases, renal diseases, respiratory diseases, and rheumatic disorders. See prescribing information for a complete list. Used primarily as an anti-inflammatory or immunosuppressant agent. May be used in conjunction with other forms of therapy, such as epinephrine for acute hypersensitivity reactions. Oral therapy should be used when appropriate.

Contraindications

Precautions

Not the drug of choice to treat acute adrenocortical insufficiency. ■ May produce hypothalamic-pituitary-adrenal (HPA) axis suppression with resulting glucocorticosteroid insufficiency in patients undergoing chronic or prolonged therapy. To avoid relative adrenocortical insufficiency, do not stop therapy abruptly; taper off. Patient is observed carefully, especially under stress, for up to 2 years; exception is very short-term therapy. ■ Increased doses of rapidly acting corticosteroids are indicated when patients on corticosteroid therapy are subjected to any unusual stress (e.g., surgery, hospitalization).These increased doses should be used before, during, and after the stressful situation. ■ Formulation may contain benzyl alcohol; see Contraindications and Maternal/Child. ■ Rare instances of anaphylactoid reactions have been reported in patients receiving corticosteroid therapy. ■ In one study, an increase in mortality was seen in patients with cranial trauma who had no other clear indication for corticosteroid treatment. Should not be used for treatment of traumatic brain injury. ■ Use with caution in patients who have had a recent MI. Ventricular free wall rupture has been reported. ■ Patients taking corticosteroids may be more susceptible to infections. Latent disease may be activated. Intercurrent infections may be exacerbated; see Contraindications. ■ Use with caution in patients with CHF, hypertension, or renal insufficiency. May affect fluid and electrolyte balance. ■ Use with caution in patients with thyroid dysfunction; see Dose Adjustments. ■ Use with caution in patients with active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis. May be at increased risk for perforation. ■ Metabolism of corticosteroids is decreased in patients with cirrhosis; effects may be enhanced. ■ Use with caution in patients at risk for osteoporosis. Corticosteroids decrease bone formation, increase bone resorption, and decrease protein matrix of the bone. May lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. ■ An acute myopathy has been reported with the use of high doses of corticosteroids. Most often seen in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) or in patients receiving concomitant therapy with neuromuscular blocking drugs. Myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Clinical improvement following discontinuation of corticosteroids may take weeks to years. ■ May induce psychological changes (e.g., depression, euphoria, insomnia, mood swings, personality changes, psychosis). May aggravate existing emotional instability or psychotic tendencies. ■ Kaposi’s sarcoma has been reported in patients receiving corticosteroid therapy, most often for chronic conditions. Clinical improvement has been seen with discontinuation of the corticosteroid. ■ Prophylactic antacids may prevent peptic ulcer complications.

Drug/lab interactions

Aminoglutethimide (Cytadren) may lead to a loss of corticosteroid-induced adrenal suppression. ■ Metabolism increased and effects reduced by hepatic enzyme–inducing agents (e.g., alcohol, barbiturates [e.g., phenobarbital], hydantoins [e.g., phenytoin (Dilantin)], rifampin [Rifadin]); dose adjustments may be required when adding or deleting from drug profile. ■ Risk of hypokalemia increased with amphotericin B or potassium-depleting diuretics (e.g., thiazides, furosemide, ethacrynic acid). Monitor potassium levels and cardiac function. Increased risk of digoxin toxicity secondary to hypokalemia. ■ May decrease effectiveness of potassium supplements; monitor serum potassium. ■ Diuretics decrease sodium and fluid retention effects of corticosteroids; corticosteroids decrease sodium excretion and diuretic effects of diuretics. ■ Use with cyclosporine in organ transplants is therapeutic but may increase cyclosporine toxicity; seizures have been reported; use caution. ■ Clearance decreased and effects increased with estrogens, oral contraceptives, triazole antifungals (e.g., itraconazole [Sporanox]), and macrolide antibiotics (e.g., azithromycin [Zithromax], erythromycin, troleandomycin [TAO]). ■ Coadministration of aprepitant (fosaprepitant [Emend]) may increase methylprednisolone levels. Dose reduction of methylprednisolone may be indicated. ■ May interact with anticoagulants, nondepolarizing muscle relaxants (e.g., atracurium [Tracrium]), or theophyllines; may inhibit or potentiate action; monitor carefully. ■ Monitor patients receiving antidiabetic agents (e.g., insulin, glyburide) or thyroid hormones carefully; dose adjustments of either or both agents may be required. ■ May antagonize effects of isoniazid and salicylates; dose adjustments may be required. ■ Administration of live virus or live-attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Inactivated vaccines may be administered, but the response to such vaccines cannot be predicted. ■ Concomitant use with NSAIDs (e.g., ibuprofen [Advil, Motrin], naproxen [Aleve, Naprosyn]) may increase the risk of adverse GI effects. ■ Concomitant use with anticholinesterase agents (e.g., neostigmine) may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. ■ Altered protein-binding capacity will impact effectiveness of this drug. ■ Corticosteroids may suppress reactions to skin tests. ■ See Dose Adjustments.

Side effects

Do occur but are usually reversible: Cushing’s syndrome; electrolyte and calcium imbalance; euphoria; glycosuria; hyperglycemia; hypersensitivity reactions, including anaphylaxis; hypertension; increased appetite; increased intracranial pressure; menstrual irregularities; peptic ulcer perforation and hemorrhage; protein catabolism; spontaneous fractures; transitory burning or tingling, sweating, headache, or weakness; thromboembolism; and many others.

Antidote

Notify the physician of any side effect. Will probably treat the side effect if necessary. Resuscitate as necessary for anaphylaxis and notify physician. Keep epinephrine immediately available.

Usual dose

Pediatric dose

Dose adjustments

Antiemetic dose may be reduced to 1 mg/kg if initial doses suppress vomiting. Initial doses may be reduced to 1 mg/kg for less emetogenic regimens. ■ Reduce initial dose by half in any patient with a CrCl less than 40 mL/min. Adjust subsequent doses as indicated. ■ Caution and lower-end dosing suggested in elderly patients. Consider potential for decreased organ function and concomitant disease or drug therapy. ■ See Drug/Lab Interactions.

Dilution

May be given undiluted if dose does not exceed 10 mg. For doses exceeding 10 mg dilute in at least 50 mL of D5W, NS, D5/¹/₂NS, R, or LR, and give as an infusion.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

Manufacturer lists as incompatible with chloramphenicol (Chloromycetin) and sodium bicarbonate.

Sources suggest the following compatibilities:

Rate of administration

Too-rapid IV injection will cause intense anxiety, restlessness, and then drowsiness.

Actions

A dopamine antagonist. Antiemetic properties appear to be the result of antagonism of central and peripheral dopamine receptors. Blocks the stimulation of medullary chemoreceptor trigger zones by dopamine. Inhibits nausea and vomiting. Increases tone and amplitude of gastric contractions, relaxes the lower pyloric sphincter and duodenal bulb, and increases peristalsis of the duodenum and jejunum, resulting in accelerated gastric emptying. Does not stimulate gastric, biliary, or pancreatic secretions. Acts even if vagal innervation not present. Action negated by anticholinergic drugs. Distributes extensively into tissues. Onset of action occurs in 1 to 3 minutes and lasts 1 to 2 hours. Average half-life is 5 to 6 hours. Excreted in urine. Secreted in breast milk.

Indications and uses

Facilitate small bowel intubation. ■ Stimulate gastric and intestinal emptying of barium to permit radiologic examination of the stomach and small intestine. ■ Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. ■ Prophylaxis of postoperative nausea and vomiting when nasogastric suction is not indicated. ■ Diabetic gastroparesis.

Contraindications

Situations in which gastric motility is contraindicated (i.e., gastric hemorrhage, obstruction, or perforation); known hypersensitivity to metoclopramide; patients with epilepsy or patients taking drugs that may also cause extrapyramidal reactions; pheochromocytoma.

Precautions

May produce sedation, extrapyramidal symptoms, or Parkinson-like symptoms, similar to those seen with phenothiazines. Use caution in patients with pre-existing disease. ■ Acute dystonic reactions (a type of extrapyramidal symptom [EPS]) are usually seen during the first 24 to 48 hours of treatment and are more common in pediatric patients, in adults under 30 years of age, and at higher doses used for prophylaxis of N/V due to chemotherapy. ■ Tardive dyskinesia may develop and is usually related to duration of treatment and total cumulative dose. Avoid use for longer than 12 weeks unless benefit outweighs risk of tardive dyskinesia. ■ Neuroleptic malignant syndrome (NMS) has been reported rarely. Potentially fatal. Discontinue metoclopramide immediately; see Monitor. ■ Produces a transient increase in plasma aldosterone; patients with cirrhosis or CHF may develop fluid retention and volume overload. If S/S occur, discontinue metoclopramide. ■ Use with caution in patients with hypertension. May cause release of catecholamines, exacerbating the condition. ■ A prolactin-elevating compound; may be carcinogenic. Risk with a single dose almost nonexistent. ■ May cause serious depression and suicidal tendencies; use extreme caution in any patient with a history of depression. ■ Patients with NADH-cytochrome b₅ reductase deficiency are at increased risk for developing methemoglobinemia and/or sulfhemoglobinemia. In patients with G6PD deficiency who develop methemoglobinemia, methylene blue treatment is not recommended. Can cause hemolytic anemia. ■ See Maternal/Child.

Drug/lab interactions

Antagonized by anticholinergic drugs (e.g., atropine) and narcotic analgesics (e.g., morphine). ■ May potentiate alcohol and cyclosporine. ■ Drugs ingested orally may be absorbed more slowly or more rapidly depending on the absorption site (e.g., inhibits cimetidine, digoxin). ■ Potentiates MAO inhibitors (e.g., selegiline [Eldepryl]); use extreme caution or do not use. ■ Insulin reactions may result from gastric stasis, making diabetic control difficult. Dose or timing of insulin may need adjustment. ■ Extrapyramidal effects may be potentiated with concomitant use of phenothiazines, butyrophenones, and thioxanthines (antipsychotic drugs). ■ Used concurrently, metoclopramide and levodopa have opposite effects on dopamine receptors; metoclopramide is inhibited and levodopa is potentiated.

Side effects

Usually mild, transient, and reversible after metoclopramide is discontinued. Hypersensitivity reactions can occur. Acute CHF, anxiety, arrhythmias, bowel disturbances, confusion, convulsions, depression (severe, may have suicidal tendencies), dizziness, drowsiness, extrapyramidal reactions, fatigue, fluid retention, hallucinations, headache, hypertension, hypotension, insomnia, methemoglobinemia in neonates, nausea, NMS (hyperthermia, muscle rigidity, altered consciousness, and evidence of autonomic instability [irregular pulse or BP, tachycardia, diaphoresis, and arrhythmias]), restlessness, sulfhemoglobinemia in adults, tardive dyskinesia. Numerous other side effects may occur.

Antidote

Notify physician of all side effects. Most will respond to a reduced dose or discontinuation of metoclopramide. Treat overdose or extrapyramidal reactions with diphenhydramine (Benadryl) or benztropine (Cogentin). Symptoms should disappear within 24 hours. To manage NMS, immediately discontinue metoclopramide. Intensive symptomatic treatment and monitoring are required. Bromocriptine (Parlodel) and dantrolene (Dantrium) have been used to treat NMS, but effectiveness not established. Discontinue therapy in patients who develop S/S of tardive dyskinesia; symptoms may resolve. Treat methemoglobinemia with IV methylene blue. Hemodialysis is not likely to be useful in an overdose. Resuscitate as necessary.

Usual dose

Dose adjustments

See Drug/Lab Interactions. ■ Not required in impaired renal function. ■ In patients with impaired hepatic function, start at a low dose and titrate upward slowly.

Dilution

May be given undiluted.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

One source suggests the following compatibilities:

Rate of administration

A single dose over 1 minute. Monitor ECG, HR, and BP and discontinue metoprolol if adverse symptoms occur (bradycardia less than 45 beats/min, heart block greater than first degree, systolic BP less than 100 mm Hg, or moderate to severe cardiac failure).

Actions

Metoprolol is a cardioselective (B₁) adrenergic receptor blocker. Its mechanism of action in patients with suspected or definite myocardial infarction is not known, but its use has been shown to reduce the 3-month mortality rate in this patient population. It reduces the incidence of recurrent myocardial infarctions and reduces the size of the infarct and the incidence of fatal arrhythmias. Reduces HR, systolic BP, and cardiac output. Well distributed throughout the body, it acts within 1 to 2 minutes and lasts about 3 to 4 hours. Maximum beta blockade is achieved in approximately 20 minutes. Metabolized in the liver by the cytochrome P₄₅₀ enzyme system, primarily CYP2D6. Excreted as metabolites in the urine. Crosses placental barrier. Secreted in breast milk.

Indications and uses

To reduce cardiac mortality in hemodynamically stable individuals with suspected or definite myocardial infarction (used in conjunction with oral metoprolol maintenance therapy). ■ Treatment of hypertension, angina pectoris, and CHF in oral dosage form.

Contraindications

HR below 45 beats/min, second- or third-degree heart block, significant first-degree heart block (PR interval equal to or greater than 0.24 second), systolic BP below 100 mm Hg, or moderate to severe cardiac failure. ■ Hypersensitivity to metoprolol or to any of the excipients. Use caution in patients with hypersensitivity to other beta-blockers (e.g., atenolol [Tenormin], esmolol [Brevibloc], propranolol). Cross-sensitivity between beta-blockers can occur. ■ Severe peripheral arterial circulatory disorders or sick sinus syndrome in patients with angina or hypertension.

Precautions

Use caution in CHF. Beta blockade may depress myocardial contractility and precipitate or exacerbate heart failure and cardiogenic shock. ■ Use caution in presence of heart failure controlled by digoxin. Both drugs slow AV conduction. Bradycardia, sinus pause, heart block, and cardiac arrest have occurred. Patients with first-degree AV block, sinus node dysfunction, or conduction disorders may be at increased risk; see Antidote. ■ May produce significant first- (PR interval equal to or greater than 0.26 second), second-, or third-degree heart block. Acute MI can also cause heart block. ■ Metoprolol decreases sinus heart rate. MI may also produce significant lowering of HR; see Antidote. ■ Routine withdrawal of chronically administered beta-blockers before major surgery is not necessary; however, the risks of general anesthesia and surgical procedures may be increased by the impaired ability of the heart to respond to reflex adrenergic stimuli. ■ Use caution in patients with a history of severe anaphylactic reactions to a variety of allergens; they may be more reactive to repeated challenge (either accidental, diagnostic, or therapeutic) and may be unresponsive to the usual doses of epinephrine used to treat hypersensitivity reactions; see Drug/Lab Interactions. ■ May mask tachycardia occurring with hypoglycemia in diabetes and tachycardia of hyperthyroidism. ■ In general, patients with bronchospastic disease should not receive beta-blockers, including metoprolol. Because of its relative beta selectivity, metoprolol may be used with extreme caution in these patients. Monitor pulmonary function closely; see Antidote. ■ Use with caution in patients with impaired hepatic function; see Dose Adjustments. ■ May cause arrhythmia, angina, MI, or death if stopped abruptly (more of an issue with chronic oral therapy); see prescribing information. ■ May cause severe bradycardia in patients with Wolff-Parkinson-White syndrome. ■ Contraindicated in patients known to have or suspected of having a pheochromocytoma. If metoprolol is required, it should be given in combination with an alpha-blocker (e.g., phenoxybenzamine [Dibenzyline]) and only after the alpha-blocker has been initiated. ■ See Drug/Lab Interactions.

Drug/lab interactions

Concurrent use with calcium channel blockers (e.g., diltiazem, verapamil) may potentiate both drugs and result in severe depression of myocardium and AV conduction and severe hypotension. ■ Concurrent use with antihypertensive agents, including alpha-adrenergic blockers (e.g., clonidine [Catapres], guanfacine [Tenex], methyldopa, reserpine), may result in excessive hypotension. Dose adjustment may be required. ■ Concurrent administration with hydralazine may decrease metabolism and increase concentrations of metoprolol. ■ Potent inhibitors of the CYP2D6 enzyme may increase plasma concentrations of metoprolol and decrease its cardioselectivity. These inhibitors include antidepressants (e.g., clomipramine [Anafranil], desipramine [Norpramin], fluoxetine [Prozac], fluvoxamine [Luvox], paroxetine [Paxil], sertraline [Zoloft], bupropion [Wellbutrin]), antipsychotics (e.g., chlorpromazine, fluphenazine, haloperidol [Haldol], thioridazine [Mellaril]), antiarrhythmics (e.g., quinidine, propafenone [Rythmol]), antiretrovirals (e.g., ritonavir [Norvir]), antihistamines (e.g., diphenhydramine [Benadryl]), antimalarials (e.g., hydroxychloroquine [Plaquenil], quinidine), allylamine antifungals (e.g., terbinafine [Lamisil]), and medications for stomach ulcers (e.g., cimetidine [Tagamet]). ■ Concurrent use within 14 days of MAO inhibitors (selegiline [Eldepryl]) may cause severe hypertension. ■ Use with sympathomimetic agents (e.g., epinephrine, norepinephrine, phenylephrine) or xanthines (e.g., aminophylline) may negate therapeutic effects of both drugs. ■ Effects of beta-adrenergic blocking agents may be decreased by anti-inflammatory drugs (e.g., NSAIDs), barbiturates, rifampin, salicylates, and others. ■ Inhalation anesthetics, phenytoin (Dilantin), and quinolone antibiotics (e.g., ciprofloxacin) may increase myocardial depressant effects and hypotension. ■ Beta-adrenergic blocking agents may be continued during the perioperative period in most patients; however, use caution with selected anesthetic agents that may depress the myocardium. ■ Potentiates effects of oral antidiabetics, catecholamine-depleting drugs (e.g., reserpine), insulin, lidocaine, and skeletal muscle relaxants; monitor carefully. Dose adjustment may be required. ■ Concurrent use with clonidine may precipitate acute hypertension if one or both agents are stopped abruptly. Withdraw metoprolol first. ■ Effects decreased when hypothyroid patient is converted to a euthyroid state; adjust dose as indicated. ■ Used concurrently with digoxin or alpha-adrenergic blockers (e.g., phentolamine [Regitine]) as indicated. ■ Use caution; both digoxin and beta-blockers (e.g., atenolol, esmolol, metoprolol, propranolol) slow AV conduction. May increase risk of bradycardia. ■ Patients taking beta-blockers who are exposed to a potential allergen may be unresponsive to the usual dose of epinephrine used to treat a hypersensitivity reaction. ■ May enhance the vasoconstrictive action of ergot alkaloids. ■ In general, withhold administration of a beta-blocker before dipyridamole testing; monitor HR carefully following dipyridamole injection.

Side effects

Abdominal pain, bradyarrhythmias, bronchospasm, cardiac failure, claudication, confusion, dizziness, dyspnea, elevated liver function tests, first-degree heart block, hallucinations, headache, hepatitis, hypotension, jaundice, nausea, nightmares, pruritus, rash, reduced libido, respiratory distress, second- or third-degree heart block, sleep disturbances, syncopal attacks, tiredness, unstable diabetes, vertigo, visual disturbances.

Antidote

For any side effect, discontinue drug and notify physician immediately. Patients with myocardial infarction may be more hemodynamically unstable; treat with caution. Use atropine (0.25 to 0.5 mg) for bradycardia or heart block; use isoproterenol with caution if atropine is not effective. Glucagon 5 to 10 mg IV may be effective if atropine and isoproterenol are not (investigational use). Transvenous cardiac pacing may be needed. Treat hypotension with IV fluids if indicated or vasopressors (dopamine or norepinephrine [Levarterenol]); treat cause of hypotension (e.g., bradycardia). Use all vasopressors with extreme caution; severe hypotension can result. Use digoxin and diuretics at first sign of cardiac failure; dobutamine, isoproterenol, or glucagon may be required. Use aminophylline or isoproterenol (with extreme care) for bronchospasm, and glucagon or IV glucose for hypoglycemia. Treat other side effects symptomatically; resuscitate as necessary.

Usual dose

May transfer to oral therapy when condition warrants (usual PO dose is 7.5 mg/kg every 6 hours).

Pediatric dose

Safety for use in infants and other pediatric patients not established, but is used for anaerobic infections; see Maternal/Child.

Dose adjustments

Reduce dose by 50% in patients with severe (Child-Pugh Class C) hepatic impairment. ■ Increase intervals in neonates; see Pediatric Dose. ■ No dose adjustment is indicated in mild to moderate impaired renal function. Recommendations vary for patients with a CrCl of less than 10 mL/min who are not on dialysis; consider reducing dose by 50% or increasing the interval to every 12 hours. ■ Dose adjustment not indicated in anuric patients; accumulated metabolites readily removed by dialysis. 40% to 65% of a metronidazole dose can be removed by dialysis depending on length of dialysis session and type of dialyzer membrane used. If metronidazole administration cannot be separated from dialysis session, consider supplemental dose following dialysis. ■ Continuous NG suction may remove sufficient metronidazole in gastric aspirate to reduce serum levels. No dose adjustment is recommended.

Dilution

All solutions are prediluted and ready to use (5 mg/mL) except Flagyl IV. The powder form (Flagyl IV) is not readily available but requires a specific dilution process. Initially add 4.4 mL SWFI or NS for injection (with or without preservative) to provide a solution with an approximate concentration of 100 mg/mL (500 mg in 5 mL). Solution must be clear. Solution will be yellow to yellow-green in color with a pH of 0.5 to 2. The desired dose of properly reconstituted solution may be further diluted with NS, D5W, or LR. Do not exceed a concentration of 8 mg/mL (500 mg in 100 mL yields a concentration of 5 mg/mL). Must be neutralized before infusion with 5 mEq of sodium bicarbonate per 500 mg metronidazole to achieve an approximate pH of 6 to 7. Mix thoroughly. CO₂ gas will be generated and may require venting. Do not use plastic containers in series connections. Risk of air embolism is present. Avoid all contact with aluminum in needles and syringes in all situations.

Compatibility (underline indicates conflicting compatibility information)

Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.

Manufacturer recommends, “Administer separately, discontinue the primary IV during administration, and do not introduce additives into the solution.” Do not use equipment containing aluminum.

One source suggests the following compatibilities:

Rate of administration

Must be given as a slow intermittent or continuous IV infusion, each single dose evenly distributed over 1 hour. Discontinue primary IV during administration.

Actions

A bactericidal agent with cytotoxic effects, active against specific obligate anaerobic bacteria and protozoa. Does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Metronidazole enters the organism by passive diffusion and is reduced. The reduced form and free radicals that are produced during the reduction reaction interact with DNA, leading to inhibition of DNA synthesis and to DNA degradation and death of bacteria. The precise mechanism of action is unclear. Metronidazole is widely distributed. Plasma concentrations are directly proportional to dose given. Onset of action is prompt. Metabolized in the liver. Half-life is 8 hours. Crosses placental and blood-brain barriers. Excreted primarily in urine, some in feces. Secreted in breast milk.

Indications and uses

Treatment of serious infections caused by susceptible strains of anaerobic bacteria, including serious intra-abdominal, skin and skin structure, gynecologic, bone and joint, CNS, and lower respiratory tract infections, bacterial septicemia, and endocarditis. Is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol, and penicillin. ■ Perioperative prophylaxis to reduce infection rates in contaminated or potentially contaminated colorectal surgery. ■ Given orally for amebiasis, giardiasis, Helicobacter pylori eradication, and other indications.

Contraindications

Hypersensitivity to metronidazole or other nitroimidazole derivatives; use of disulfiram within the last 2 weeks; use of alcohol or products containing propylene glycol during and for at least 3 days after therapy with metronidazole.

Precautions

A mixed (anaerobic/aerobic) infection will require use of additional antibiotics targeted for treatment of the aerobic infection. ■ Sensitivity studies indicated to determine susceptibility of the causative organism to metronidazole. ■ To reduce the development of drug-resistant bacteria and maintain its effectiveness, metronidazole should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria. ■ Avoid prolonged use of the drug; superinfection caused by overgrowth of nonsusceptible organisms may result. ■ Symptoms of candidiasis may be exacerbated and require treatment. ■ Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions have been seen on MRI. Generally reversible within days to weeks after metronidazole is discontinued. ■ Optic neuropathy and peripheral neuropathy (mainly sensory with S/S of numbness or paresthesia of extremities) have been reported. ■ May cause seizures. ■ Aseptic meningitis has been reported. Symptoms may occur within hours of dose administration and generally resolve after metronidazole is discontinued. ■ Use caution in patients predisposed to edema and/or taking corticosteroids, in patients with impaired cardiac function (contains 27 to 28 mEq sodium/Gm), CNS disease, hepatic or renal impairment, or a history of blood dyscrasias. ■ Clostridium difficile–associated diarrhea (CDAD) has been reported. May range from mild diarrhea to fatal colitis. Consider in patients who present with diarrhea during or after treatment with metronidazole. ■ Carcinogenic in rodents; avoid unnecessary use and restrict use to approved indications.

Drug/lab interactions

Avoid alcohol and alcohol-containing preparations for at least 3 days after taking any dose of metronidazole; a disulfiram-like reaction (abdominal cramps, flushing, headaches, nausea and vomiting) may occur. ■ Avoid administration of metronidazole to patients who have taken disulfiram within the last 2 weeks. Psychotic reactions have been reported. ■ Concurrent use with drugs that induce microsomal enzyme activity (e.g., phenobarbital, phenytoin [Dilantin]) may increase metabolism of metronidazole and decrease plasma levels. ■ Administration with drugs that inhibit microsomal liver enzyme activity (e.g., cimetidine [Tagamet]) may prolong the half-life of metronidazole and increase metronidazole plasma levels. ■ May decrease clearance and increase serum concentration of phenytoin. ■ May decrease metabolism and increase anticoagulant effects of warfarin (Coumadin). Monitor PT/INR periodically. ■ May increase lithium levels and cause toxicity. ■ May increase plasma concentrations of busulfan, increasing the risk of serious busulfan toxicity. Avoid concomitant use if possible. If concomitant administration is medically necessary, monitor busulfan plasma concentration and adjust busulfan dose accordingly. ■ May interfere with selected chemistry studies (e.g., AST, ALT, LDH, triglycerides, glucose hexokinase).

Side effects

The most serious side effects include aseptic meningitis, convulsive seizures, encephalopathy, and optic and peripheral neuropathy. Abdominal cramping; anorexia; ataxia; CDAD; confusion; constipation; cystitis; darkened deep red urine; decreased libido; depression; diarrhea; dizziness; dryness of the mouth, vagina, or vulva; dysarthria; dysuria; epigastric distress; fever; fleeting joint pain; flushing; furry tongue; glossitis; headache; incontinence; insomnia; irritability; metallic taste (expected); nasal congestion; nausea; neutropenia (reversible); numbness; painful coitus; pancreatitis; paresthesia; pelvic pressure; polyuria; proctitis; pruritus; psychosis; rash; Stevens-Johnson syndrome; stomatitis; syncope; thrombocytopenia (reversible); thrombophlebitis; toxic epidermal necrolysis; T-wave flattening; urticaria; vomiting; and weakness have occurred.

Antidote

Notify physician of all side effects. Treatment will be symptomatic and supportive. Evaluate risk versus benefit of continuing therapy in patients who develop abnormal neurologic S/S (e.g., encephalopathy, seizures, or signs of peripheral neuropathy). Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. Removed by hemodialysis. Treat anaphylaxis and resuscitate as necessary.

Usual dose

Pediatric dose

Recommended doses for pediatric patients based on indication and weight are outlined in the following chart.

Micafungin Dosage in Pediatric Patients 4 Months of Age or Older
Indication	Pediatric Dose Given Once Daily
	30 kg or less	Greater than 30 kg
Treatment of candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses	2 mg/kg (maximum daily dose 100 mg)
Treatment of esophageal candidiasis	3 mg/kg	2.5 mg/kg (maximum daily dose 150 mg)
Prophylaxis of Candida infections in HSCT recipients	1 mg/kg (maximum daily dose 50 mg)

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