Antibacterial (penicillinase-resistant penicillin)
pH 6 to 8.5
Usual dose
500 mg to 1 Gm every 4 hours. Up to 12 Gm in 24 hours has been used in severe infections. Continue therapy for at least 48 hours after patient is afebrile and asymptomatic and cultures are negative. Usual duration of therapy is at least 14 days for severe staphylococcal infections and longer (4 to 6 weeks) for endocarditis and osteomyelitis.
Endocarditis, meningitis, osteomyelitis, or pericarditis:
1.5 to 2 Gm every 4 to 6 hours.
Pediatric dose
Safety and effectiveness for use in pediatric patients not established. All pediatric doses are unlabeled; see Maternal/Child. Limited clinical experience with IV route in neonates and infants. Maximum dose is 12 Gm/24 hr.
Pediatric patients less than 40 kg and over 1 month of age:
Moderate infections:
50 to 100 mg/kg/24 hr in equally divided doses every 6 hours (12.5 to 25 mg/kg every 6 hours).
Serious infections (e.g., osteomyelitis, pericarditis, endocarditis):
100 to 200 mg/kg/24 hr in equally divided doses every 4 to 6 hours (16.6 to 33.3 mg/kg every 4 hours or 25 to 50 mg/kg every 6 hours).
Neonatal dose
Safety and effectiveness for use in neonates not established. All pediatric doses are unlabeled; see Maternal/Child. Limited clinical experience with IV route in neonates and infants.
10 to 20 mg/kg every 8 to 12 hours, or 25 mg/kg with the interval adjusted based on age and weight as follows:
0 to 7 days of age and under 2,000 gm:
Every 12 hours.
Over 7 days of age and under 1,200 gm:
Every 12 hours.
Over 7 days of age and 1,200 to 2,000 gm:
Every 8 hours.
0 to 7 days of age and over 2,000 gm:
Every 8 hours.
Over 7 days of age and over 2,000 gm:
Every 6 hours.
Increase dose to 50 mg/kg every 6, 8, or 12 hours in meningitis.
Dose adjustments
Dose adjustment not required for patients with renal dysfunction, including those receiving hemodialysis. ■ Measure nafcillin serum levels and adjust dose accordingly in patients with hepatic insufficiency and renal failure.
Dilution
Each 500-mg vial is diluted with 1.7 mL of SWFI (1-Gm vial with 3.4 mL, 2-Gm vial with 6.8 mL). Each 1 mL equals 250 mg. Further dilute each dose with a minimum of 15 to 30 mL of SWFI, NS, or 1/2NS, or other compatible IV solutions (see chart on inside back cover or literature). Concentration should be 2 to 40 mg/mL. Available prediluted and in ADD-Vantage vials for use with ADD-Vantage infusion containers. May be given through Y-tube, three-way stopcock, or with additive tubing, or may be added to larger volume of compatible solutions.
Filters:
Not required by manufacturer. Premixed and frozen solutions are filtered during manufacturing.
Storage:
Store unopened vials at CRT. Refrigerate unused medication after initial dilution and discard after 7 days. Stable in specific solutions at concentrations of 2 to 40 mg/mL for 24 hours at room temperature and 96 hours if refrigerated. Frozen, premixed solutions should be stored at −20° C (−4° F). Thaw at room temperature or under refrigeration. Thawed solutions are stable for 72 hours at RT or 21 days refrigerated. Do not refreeze.
Compatibility (underline indicates conflicting compatibility information)
Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.
Inactivated in solution with aminoglycosides (e.g., amikacin, gentamicin). Do not mix in the same solution. Appropriate spacing and/or separate sites required. See Drug/Lab Interactions.
One source suggests the following compatibilities:
Additive:
Aminophylline, chloramphenicol (Chloromycetin), chlorothiazide (Diuril), dexamethasone (Decadron), dextran 40, diphenhydramine (Benadryl), ephedrine sulfate, heparin, lidocaine, potassium chloride (KCl), prochlorperazine (Compazine), sodium bicarbonate, sodium lactate, verapamil.
Y-site:
Acyclovir (Zovirax), atropine, cyclophosphamide (Cytoxan), diazepam (Valium), diltiazem (Cardizem), enalaprilat (Vasotec IV), esmolol (Brevibloc), famotidine (Pepcid IV), fentanyl, fluconazole (Diflucan), foscarnet (Foscavir), heparin, hydromorphone (Dilaudid), magnesium sulfate, morphine, nicardipine (Cardene IV), propofol (Diprivan), theophylline, vancomycin, zidovudine (AZT, Retrovir).
Rate of administration
IV injection:
Each 500 mg or fraction thereof properly diluted over 5 to 10 minutes.
Intermittent IV:
Administration over 30 to 60 minutes may decrease incidence of thrombophlebitis.
Infusion:
When diluted in large volumes of infusion fluids, give at rate prescribed.
Actions
A semi-synthetic penicillinase-resistant penicillin, used for its bactericidal activity against gram-positive organisms, primarily penicillinase-producing staphylococci. Mode of action involves inhibition of bacterial cell wall biosynthesis. Highly resistant to inactivation by staphylococcal penicillinase. Readily distributes into most body fluids and tissues except spinal fluid. Binds to serum proteins, primarily albumin. Mainly eliminated by hepatic inactivation and excretion in bile; a small amount is excreted in urine. Half-life is 30 to 60 minutes. Crosses the placental barrier. Secreted in breast milk.
Indications and uses
Treatment of infections caused by penicillinase-producing staphylococci.
Contraindications
Known hypersensitivity to any penicillin or cephalosporin (not absolute); see Precautions. Prediluted solutions containing dextrose may be contraindicated with known allergies to corn products.
Precautions
Sensitivity studies necessary to determine susceptibility of the causative organism to nafcillin. Nafcillin should not be used in infections caused by an organism susceptible to penicillin G or due to an organism other than a resistant staphylococcus. Modify antimicrobial treatment as indicated by C/S. ■ To reduce the development of drug-resistant bacteria and maintain its effectiveness, nafcillin should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria. ■ Use with caution in patients with both impaired hepatic and renal function; elevated serum concentrations may cause neurotoxic reactions. See Dose Adjustments. ■ Hypersensitivity reactions, including fatalities, have been reported in patients receiving beta-lactam antibacterial drugs; most likely to occur in patients with a history of penicillin hypersensitivity or sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity experiencing severe reactions when treated with cephalosporins. Check history of previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Actual incidence of cross-allergenicity not established but may be more common with first-generation cephalosporins. ■ Avoid prolonged use of the 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 nafcillin. ■ Manufacturer’s premixed solutions contain dextrose; may be contraindicated in patients with an allergy to corn or corn products.
Monitor:
Obtain baseline CBC with differential and monitor during treatment. Monitor urinalysis, SCr, BUN, ALT, and AST periodically, especially with prolonged treatment. ■ Watch for early symptoms of a hypersensitivity reaction, especially in individuals with a history of allergic problems. ■ May cause thrombophlebitis, especially in the elderly or with too-rapid injection. Limit IV treatment to 24 to 48 hours when possible. Change to oral therapy as soon as practical. ■ Electrolyte imbalance and cardiac irregularities from sodium content are possible. Contains up to 3.3 mEq sodium/Gm. May aggravate CHF. Observe for hypokalemia. ■ See Drug/Lab Interactions.
Patient education:
May require alternate birth control. ■ Promptly report diarrhea or bloody stools that occur during treatment or up to several months after an antibiotic has been discontinued; may indicate CDAD and require treatment.
Maternal/child:
Category B: use only if clearly needed. ■ Safety and effectiveness for use in pediatric patients not established, but it is used; see Pediatric Dose. ■ May cause diarrhea, candidiasis, or allergic response in nursing infants. ■ Elimination rate markedly reduced in neonates and infants due to immature hepatic and renal function.
Elderly:
Response similar to that seen in younger adults. Consider age-related organ impairment and concomitant disease or drug therapy. ■ May be at increased risk for thrombophlebitis. ■ See Precautions/Monitor and Dose Adjustments.
Drug/lab interactions
May be antagonized by bacteriostatic antibiotics (e.g., chloramphenicol, erythromycin, tetracyclines); may interfere with bactericidal action. ■ Potentiated by probenecid; toxicity may result. ■ Synergistic when used in combination with aminoglycosides (e.g., amikacin, gentamicin). Synergism may be inconsistent; see Compatibility. ■ Concomitant use with beta-adrenergic blockers (e.g., propranolol) may interfere with the treatment of a hypersensitivity reaction to nafcillin. ■ Risk of bleeding with anticoagulants (e.g., heparin) is increased. ■ May decrease serum levels and effectiveness of cyclosporine (Sandimmune). ■ Inhibits effectiveness of oral contraceptives; breakthrough bleeding or pregnancy could result. ■ High doses (9 to 12 Gm daily) may decrease serum half-life of warfarin (Coumadin); monitor PT up to 30 days after nafcillin completed. ■ May reduce effectiveness of nifedipine (Procardia XL) by reducing its serum plasma levels. ■ May cause false values in common lab tests; see literature.
Side effects
Bleeding abnormalities, bone marrow suppression (e.g., agranulocytosis, neutropenia), diarrhea, hypersensitivity reactions (e.g., anaphylaxis, bronchospasm, pruritus, rash, serum sickness–like symptoms, urticaria [may be immediate or delayed]), interstitial nephritis, local reactions (e.g., pain, phlebitis, thrombophlebitis, and occasionally skin sloughing with extravasation), nausea and vomiting, and renal tubular damage have been reported. CDAD and hypersensitivity myocarditis (fever, eosinophilia, rash, sinus tachycardia, ST-T changes, and cardiomegaly) can occur. Higher-than-normal doses may cause neurologic adverse reactions, including convulsions, especially with concomitant impaired hepatic insufficiency and renal dysfunction.
Antidote
Notify physician immediately of any adverse symptoms. For severe symptoms discontinue the drug, treat hypersensitivity reaction (antihistamines, epinephrine, corticosteroids), and resuscitate as necessary. Hemodialysis or peritoneal dialysis is minimally effective in overdose. Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. Mild cases may respond to drug discontinuation alone.
Nalbuphine hydrochloride
(NAL-byoo-feen hy-droh-KLOR-eyed)
Narcotic analgesic (agonist-antagonist)
Anesthesia adjunct
pH 3.5 to 3.7
Usual dose
Pain control:
10 mg/70 kg. May repeat every 3 to 6 hours. In nontolerant patients, the recommended single maximum dose is 20 mg. Maximum total daily dose is 160 mg. Adjust dose and interval according to severity of pain, physical status of patient, and other medications administered concomitantly; see Dose Adjustments.
Adjunct to balanced anesthesia:
A loading dose of 300 mcg (0.3 mg) to 3 mg/kg over 10 to 15 minutes. Maintain desired level of balanced anesthesia with 250 to 500 mcg/kg (0.25 to 0.5 mg/kg) as required. Administered only under the direction of the anesthesiologist.
Dose adjustments
In patients dependent on opioids, initiate a dose of nalbuphine at one fourth the usual dose if their previous medication was a narcotic. Observe for symptoms of withdrawal. Increase to effective dose gradually. ■ Reduced dose may be required in the elderly or debilitated, in impaired liver or renal function, in patients with limited pulmonary reserve, and in the presence of other CNS depressants. ■ See Drug/Lab Interactions.
Dilution
May be given undiluted.
Filters:
No data available from manufacturer.
Storage:
Store at CRT. Avoid freezing and/or prolonged exposure to light.
Compatibility
Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.
Manufacturer lists as incompatible with nafcillin (Nallpen) and ketorolac (Toradol).
One source suggests the following compatibilities:
Solution:
D5NS, D10W, LR, NS.
Y-site:
Acetaminophen (Ofirmev), acyclovir (Zovirax), amifostine (Ethyol), aztreonam (Azactam), bivalirudin (Angiomax), cisatracurium (Nimbex), cladribine (Leustatin), dexmedetomidine (Precedex), etoposide phosphate (Etopophos), fenoldopam (Corlopam), filgrastim (Neupogen), fludarabine (Fludara), gemcitabine (Gemzar), granisetron (Kytril), hetastarch in electrolytes (Hextend), linezolid (Zyvox), melphalan (Alkeran), oxaliplatin (Eloxatin), paclitaxel (Taxol), propofol (Diprivan), remifentanil (Ultiva), teniposide (Vumon), thiotepa, vinorelbine (Navelbine).
Rate of administration
Pain control:
Each 10 mg or fraction thereof over 3 to 5 minutes. Frequently titrated according to symptom relief and respiratory rate.
Anesthesia adjunct:
See Usual Dose.
Actions
A synthetic narcotic agonist-antagonist analgesic. Binds to kappa, mu, and delta receptors. Acts as an agonist at kappa receptors and as a partial antagonist at mu receptors. It equals morphine in analgesic effect. Does produce respiratory depression, but this does not increase markedly with increased doses. Onset of pain relief occurs within 2 to 3 minutes and lasts about 3 to 6 hours. Metabolized in the liver. Some excretion in urine. Crosses the placental barrier. Secreted in breast milk.
Indications and uses
Relief of moderate to severe pain. ■ Preoperative and postoperative analgesia. ■ Surgical anesthesia supplement. ■ Obstetric analgesia during labor and delivery.
Unlabeled uses:
10 mg SC to reduce pruritus from epidural morphine.
Contraindications
Hypersensitivity to nalbuphine or its components.
Precautions
May precipitate withdrawal symptoms if stopped too quickly after prolonged use or if patient has been on opiates. ■ Use caution in patients with impaired respiration (e.g., from other medications, uremia, asthma, severe infection, cyanosis, or respiratory obstruction); see Dose Adjustments. ■ Use caution in patients with myocardial infarction who have nausea and vomiting or compromised cardiac function; effect on heart not fully evaluated. ■ Use caution in ambulatory patients; see Patient Education. ■ Use caution in patients with head injuries, intracranial lesions, or pre-existing increases in intracranial pressure. Nalbuphine may elevate CSF pressure and may produce effects that can obscure the clinical course of patients with head injuries (e.g., pupillary changes, sedation). ■ Use caution in patients with a history of drug abuse or emotional instability; close monitoring is required. ■ Use caution in the elderly and debilitated and in patients with renal or hepatic impairment; see Dose Adjustments. ■ Use caution in patients about to undergo surgery of the biliary tract. Can cause spasm of the sphincter of Oddi. ■ Administration during labor has caused severe fetal bradycardia; naloxone may reverse effects; see Maternal/Child. ■ Should be administered as a supplement to general anesthesia only by persons specifically trained in the use of IV anesthetics and in the management of the respiratory effects of potent opioids. ■ When used with anesthesia, a high incidence of bradycardia has been reported in patients who did not receive atropine preoperatively.
Monitor:
Naloxone, oxygen, and controlled respiratory equipment must be available. ■ Observe frequently; monitor vital signs. ■ Keep patient supine to minimize side effects; orthostatic hypotension and fainting may occur. Observe closely during ambulation. ■ Pain control usually more effective with routinely administered doses. Determine appropriate interval through clinical assessment ■ See Drug/Lab Interactions.
Patient education:
Avoid use of alcohol or other CNS depressants (e.g., antihistamines, diazepam [Valium]). ■ Request assistance for ambulation. ■ Use caution performing any task that requires alertness; may cause dizziness, euphoria, and sedation. ■ May be habit forming. Can cause withdrawal if stopped too quickly after prolonged use or if other opioids are used.
Maternal/child:
Category B: use during pregnancy (other than labor and delivery) only if benefits justify risks. Take appropriate measures (e.g., fetal monitoring) to detect and manage potential adverse effects to the fetus. ■ Safety for use during breast-feeding not established. ■ Fetal and neonatal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia have been reported. Maternal or neonatal administration of naloxone may reverse these effects. Fetal death has been reported when mothers received nalbuphine during labor and delivery. Use during labor and delivery only if clearly indicated and if benefit outweighs risk. Newborns should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias if nalbuphine has been used. ■ Not recommended for pediatric patients under 18 years of age.
Elderly:
May be more sensitive to effects (e.g., respiratory depression, constipation, dizziness, urinary retention). ■ Analgesia should be effective with lower doses. ■ Consider age-related organ impairment.
Drug/lab interactions
Potentiated by cimetidine (Tagamet), phenothiazines (e.g., chlorpromazine [Thorazine]), by other CNS depressants such as narcotic analgesics, general anesthetics, alcohol, anticholinergics, antihistamines, barbiturates, hypnotics, neuromuscular blocking agents (e.g., atracurium [Tracrium]), psychotropic agents, and sedatives. Reduced doses of both drugs may be indicated. ■ May decrease analgesic effects of other narcotics; avoid concurrent use. ■ Plasma amylase and lipase determinations may be unreliable for 24 hours following narcotic administration. ■ Depending on the test used, nalbuphine may interfere with enzymatic methods for the detection of opiates. Consult test manufacturer’s literature.
Side effects
Abdominal pain, agitation, anaphylaxis, anxiety, blurred vision, bradycardia, clammy skin, dizziness, dry mouth, fever, headache, hypertension, hypotension, injection site reaction, nausea, psychotomimetic effect (symptoms resembling a psychosis), pulmonary edema, respiratory depression, sedation, seizures, symptoms associated with histamine release, tachycardia, tremor, urinary urgency, vertigo, vomiting.
Antidote
With increasing severity of any side effect or onset of symptoms of overdose, discontinue the drug and notify the physician. Naloxone hydrochloride will reverse severe reactions. A patent airway, artificial ventilation, oxygen therapy, and other symptomatic treatment (e.g., fluids, vasopressors) must be instituted promptly.
Naloxone hydrochloride
(nal-OX-ohn hy-droh-KLOR-eyed)
Antidote
Narcotic antagonist
pH 3 to 4
Usual dose
Narcotic overdose:
0.4 to 2 mg. Repeat in 2 to 3 minutes if indicated. The diagnosis of narcotic overdose should be questioned if no response is observed after 10 mg of naloxone. If effective, dosage may be repeated as necessary for recurrence of symptoms.
Postoperative narcotic depression:
0.1 to 0.2 mg at 2- to 3-minute intervals to desired response. Titrate to avoid excessive reduction of narcotic analgesic action.
Challenge test for suspected opioid dependence:
0.2 mg. Observe for 30 seconds for S/S of withdrawal (e.g., abdominal cramps, diaphoresis, dysphoria, nausea and vomiting, rhinorrhea). If no evidence of withdrawal, inject 0.6 mg of naloxone and observe for an additional 20 minutes. Monitor VS and observe patient again for S/S of opiate withdrawal.
Pediatric dose
Ampules containing 0.02 mg/mL are available, but larger doses are frequently required. Adult strength is often used to reduce amount of injection and to effect desired response, which may require increased or repeat doses. One source states, “Up to 10 times a dose has been required.”
Narcotic overdose:
Less than 20 kg:
0.01 to 0.1 mg/kg of body weight initially. Based on estimated degree of overdose and respiratory depression. May repeat every 2 to 3 minutes. May dilute with SWFI. American Academy of Pediatrics recommends 0.1 mg/kg. Manufacturer recommends 0.01 mg/kg.
Over 20 kg or over 5 years of age:
2 mg. Repeat every 2 to 3 minutes as needed. A continuous infusion may be used after initial effective dose. Add 75% to 100% of effective dose to a specific amount of IV fluid and infuse evenly distributed over 1 hour. For some overdoses (e.g., methadone), weaning in 50% increments may take up to 48 hours. For others, 6 to 12 hours is adequate. If symptoms recur, rebolus and go back to 100%.
Postoperative narcotic depression:
0.005 to 0.01 mg IV at 2- to 3-minute intervals to desired response.
Neonatal dose
Neonatal opiate depression:
Administration into umbilical vein is preferred. 0.01 to 0.1 mg/kg of body weight initially. Based on estimated degree of overdose and respiratory depression. May repeat every 2 to 3 minutes to achieve a satisfactory response. May dilute with SWFI. American Academy of Pediatrics recommends 0.1 mg/kg repeated every 2 to 3 minutes. Manufacturer recommends 0.01 mg/kg repeated every 2 to 3 minutes. Another source suggests an initial dose of 0.01 mg/kg. If response is not satisfactory, increase subsequent doses to 0.1 mg/kg.
Dilution
May be given undiluted, diluted with SWFI, or further diluted in NS or D5W and given as an infusion (2 mg in 500 mL equals a concentration of 0.004 mg/mL). Discard infusions after 24 hours.
Storage:
Store below 40° C. Protect from light.
Compatibility
Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.
Manufacturer lists as incompatible with bisulfites, sulfites, long-chain or high-molecular-weight anions, solutions with an alkaline pH.
One source suggests the following compatibilities:
Additive:
Verapamil.
Y-site:
Fenoldopam (Corlopam), linezolid (Zyvox), propofol (Diprivan).
Rate of administration
Each 0.4 mg or fraction thereof over 15 seconds. Titrate infusion to patient response.
Actions
A potent narcotic antagonist. Overcomes effects of narcotic overdose including respiratory depression, sedation, and hypotension. Unlike other narcotic antagonists, it does not have any narcotic effect itself. Onset of action is within 2 minutes. Duration of action is dependent on dose and route of naloxone administration. Requirement for repeat doses is dependent on amount, type, and route of narcotic administration. Metabolized in the liver and excreted in urine.
Indications and uses
Reversal of narcotic depression. ■ Antidote for natural (e.g., morphine) and synthetic narcotics (e.g., butorphanol, methadone, nalbuphine, and pentazocine). ■ Diagnosis of suspected opioid tolerance or acute opiate overdose.
Unlabeled uses:
Reversal of alcoholic coma and improvement of circulation in refractory shock.
Contraindications
Known hypersensitivity to naloxone. ■ The naloxone challenge test should not be performed in patients showing S/S of withdrawal or whose urine contains opioids.
Precautions
Does not produce respiratory depression with nonnarcotic drug overdose, a beneficial action. ■ It is ineffective against respiratory depression caused by barbiturates, anesthetics, other nonnarcotic agents, or pathologic conditions. ■ Will precipitate acute withdrawal symptoms in narcotic addicts; use caution, especially in newborns of narcotic-dependent mothers. ■ Use caution in cardiac disease patients or those receiving cardiotoxic drugs.
Monitor:
Symptomatic treatment with oxygen and artificial ventilation as necessary should be continued until naloxone is effective. Observe patient continuously. Duration of narcotic action may exceed that of naloxone.
Maternal/child:
Category B: use in pregnancy and breast-feeding only when clearly needed. Safety for use not established. ■ See Precautions.
Drug/lab interactions
Specific information not available.
Side effects
Hypertension, irritability and increased crying in the newborn, nausea and vomiting, sweating, tachycardia, tremulousness. Overdose postoperatively may result in excitement, hypertension, hypotension, pulmonary edema, reversal of analgesia, ventricular tachycardia and fibrillation.
Antidote
Notify the physician of any side effect. Treatment will probably be symptomatic. Resuscitate as necessary.
Natalizumab 
(nah-tah-LIZZ-u-mab)
Tysabri
Monoclonal antibody
Immunomodulator
pH 6.1
Usual dose
Multiple sclerosis (MS):
300 mg as an infusion every 4 weeks.
Crohn’s disease (CD):
300 mg as an infusion every 4 weeks. Discontinue if no benefit is seen after 12 weeks of therapy. For patients with CD who initiate natalizumab therapy while on chronic corticosteroids, begin steroid tapering as soon as therapeutic benefit of natalizumab has occurred. Discontinue natalizumab if the patient cannot be tapered off steroids within 6 months. Consider discontinuing therapy in patients who require more than 3 months of steroid use (excluding the original 6-month taper) in a calendar year to control their CD. Aminosalicylates may be continued during therapy with natalizumab.
Dose adjustments
None indicated. Pharmacokinetics has not been studied in patients with renal or hepatic insufficiency.
Dilution
Available in 300 mg/15 mL single-use vials. Withdraw 15 mL of concentrate (300 mg) from the vial and inject into 100 mL of NS. Gently invert to mix completely. Do not shake. No other IV diluents may be used to prepare the solution. Solution is a colorless, clear to slightly opalescent concentrate. Do not use if particulates are present or if solution is discolored.
Filters:
Use of filtration devices during administration not evaluated.
Storage:
Refrigerate vials at 2° to 8° C (36° to 46° F). Do not use beyond the expiration date on the vial. Do not shake or freeze. Protect from light. Following dilution, solution should be infused immediately. However, it may be refrigerated and used within 8 hours of preparation. If refrigerated, allow to warm to room temperature before infusion.
Compatibility
Manufacturer states, “Other medications should not be injected into infusion set side ports or mixed with natalizumab.” Flush line with NS before and after infusion.
Rate of administration
Do not administer as an IV push or bolus injection. Infuse over approximately 1 hour. Flush line with NS before and after infusion.
Actions
A recombinant humanized IgG4κ monoclonal antibody produced in murine myeloma cells. An integrin receptor antagonist. Natalizumab is thought to bind to a subunit on the surface of all leukocytes except neutrophils and inhibit the adhesion of leukocytes to their counterreceptors. The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is present on vascular endothelial cells of the GI tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. Specific mechanisms of how natalizumab exerts its effects in MS and CD have not been fully defined. In multiple sclerosis (MS), lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves the interaction between adhesion molecules on inflammatory cells and their counterreceptors on the endothelial cells of the vessel wall. The clinical effect of natalizumab in MS may be secondary to blockade of the molecular interaction of α4β1 integrins expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. In clinical trials, natalizumab reduced the rate of clinical relapse and the appearance of new or newly enlarging T2 hyperintense lesions on MRI studies. The number of gadolinium-enhancing lesions on the 1-year MRI scan follow-up was also reduced. In Crohn’s disease (CD), the α4β7 integrin with the endothelial receptor MAdCAM-1 expression has been found to be increased at active sites of inflammation in the mucosa and to contribute to the inflammatory response characteristic of CD. It is mainly expressed on gut endothelial cells. The action of natalizumab may be secondary to blockade of molecular interaction of the α4β7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. Distribution is limited primarily to vascular space (plasma volume). Half-life is 3 to 17 days.
Indications and uses
Monotherapy for the treatment of patients with relapsing forms of multiple sclerosis (MS). ■ Induction and maintenance of clinical response and remission in adults with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional therapy and inhibitors of TNFα (e.g., infliximab [Remicade]). Should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine [Sandimmune], or methotrexate) or inhibitors of TNFα; see Precautions.
Contraindications
Hypersensitivity to natalizumab or any of its components, patients who have or have had progressive multifocal leukoencephalopathy (PML).
Precautions
Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), a rare opportunistic viral infection of the brain caused by the JC virus (JCV) that usually leads to death or severe disability. PML typically occurs only in patients who are immunocompromised. Risk factors for the development of PML include duration of therapy (especially beyond 2 years), prior use of immunosuppressants (e.g., azathioprine, cyclophosphamide [Cytoxan], methotrexate, mitoxantrone [Novantrone], or mycophenolate [CellCept]), and the presence of anti-JVC antibodies. Patients who are anti–JCV antibody positive have a higher risk of developing PML. These factors should be considered in the context of expected benefits when initiating and continuing treatment with natalizumab. ■ There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. Because of the risk of PML, natalizumab is available only through a special restricted distribution program called the TOUCH™ Prescribing Program. See prescribing information, or contact the manufacturer for specific details and requirements. ■ Anti-JCV testing should not be used to diagnose PML. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past. Consider testing patients before treatment or during treatment if antibody status is unknown. Patients who test negative for anti-JCV antibodies are still at risk for the development of PML because of the potential for a new JCV infection or a false-negative test result. Periodic retesting of antibody status should be considered in patients previously determined to be anti–JCV antibody negative. Anti–JCV testing should not be performed for at least 2 weeks after plasma exchange due to the removal of antibodies from the serum. ■ PML has been reported after discontinuation of natalizumab in patients who did not have findings suggestive of PML at the time of discontinuation. ■ Patients who develop PML and have discontinued natalizumab have developed immune reconstitution inflammatory syndrome (IRIS). In most cases IRIS occurred after plasma exchange was used to eliminate circulating natalizumab. This syndrome has not been seen in patients discontinuing treatment for reasons unrelated to PML. ■ Has been associated with hypersensitivity reactions, including anaphylaxis. Reactions usually occur within 2 hours of the start of the infusion. Generally associated with antibodies to natalizumab. ■ Anti-natalizumab antibodies have been detected in some patients. Persistently positive antibodies were associated with a substantial decrease in effectiveness and an increase in infusion-related reactions. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Patients who receive therapeutic monoclonal antibodies, including natalizumab, after an extended period without treatment may be at increased risk of hypersensitivity reactions with re-exposure. Consider testing for the presence of antibodies in patients who want to resume therapy after a dose interruption. ■ Effects on immune system may increase the risk of infection, including opportunistic infection. ■ Liver injury has been reported; it has occurred as early as 6 days after the first dose and after multiple doses. The combination of ALT, AST, and bilirubin elevations without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for liver transplantation. ■ Risk for developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses is increased. Serious, life-threatening, and sometimes fatal cases have been reported. ■ No data available on secondary transmission of infections by live virus vaccines.
Monitor:
Obtain baseline CBC and differential. Monitor periodically during treatment. ■ Obtain a baseline MRI before initiating treatment and periodically throughout treatment. In MS patients it may be helpful in differentiating subsequent MS symptoms from PML and assessing disease progression. In CD patients it may be helpful in distinguishing pre-existing lesions from newly developed lesions. ■ Consider determining anti-JCV antibody status before initiating natalizumab. Reassess status periodically; see Precautions. ■ Observe patients during the infusion and for 1 hour after the infusion is complete. Discontinue infusion at the first sign of any hypersensitivity reaction (e.g., chest pain, dizziness, dyspnea, fever, flushing, hypotension, nausea, pruritus, rash, rigors, urticaria). ■ Antibodies detected within the first 6 months of therapy may be transient and disappear. Repeat testing in 3 months. If antibodies are persistent, consider risk versus benefit of continued therapy; see Precautions. ■ Monitor for S/S of infection. ■ Monitor for signs of clinical relapse. ■ Assess neurologic status frequently. S/S associated with PML are diverse and occur over days to weeks. May include progressive weakness on one side of the body, clumsiness of limbs, disturbances of vision, or changes in thinking, memory, and orientation leading to confusion and personality changes. Progression of deficits usually leads to severe disability or death over weeks to months. Withhold natalizumab if PML is suspected. ■ Use of a gadolinium-enhanced MRI scan of the brain is recommended for diagnosis of PML and, when indicated, CSF analysis for JC viral DNA. If clinical suspicion of PML remains after initial evaluations are negative, continue to withhold natalizumab, and repeat evaluations. Continue to monitor for S/S suggestive of PML for approximately 6 months after discontinuation of natalizumab. ■ Monitor for S/S of IRIS; may occur within days to weeks after plasma exchange. IRIS presents as a clinical decline in condition (may occur after clinical improvement); decline may be rapid and cause serious neurologic complications or death. Associated with characteristic changes in the MRI. ■ Monitor for S/S of meningitis and encephalitis (e.g., confusion, fever, headache). ■ Monitor for S/S of liver injury (e.g., elevated bilirubin or liver function tests, jaundice).
Patient education:
Read medication guide carefully. ■ Review medical conditions and medications with health care provider. ■ Promptly report any new medical problems (e.g., new or sudden change in thinking, eyesight, balance, or strength). ■ Report infections. ■ Promptly report S/S of hepatotoxicity (e.g., anorexia, dark urine, fatigue, jaundice, right upper abdominal discomfort), meningitis, or encephalitis (e.g., confusion, fever, headache). ■ Immediately report any symptoms of infusion or hypersensitivity reactions (e.g., difficulty breathing, dizziness, feeling faint, itching, nausea). ■ Discuss potential risks and benefits of treatment (e.g., risk of PML). ■ Your physician may order a blood test to see if you have ever been exposed to JCV. Risk of PML is greatest if you have all three known risk factors; see Precautions. ■ Scheduled follow-up visits are required as part of the TOUCHTM Program. ■ PML has been reported following discontinuation of natalizumab. Monitor for S/S suggestive of PML for approximately 6 months after discontinuation of therapy.
Maternal/child:
Category C: use during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman becomes pregnant while taking natalizumab, encourage enrollment in TYSARBI Pregnancy Exposure Registry. ■ Has been detected in breast milk. Risk of this exposure to infant is unknown. ■ Safety and effectiveness in pediatric patients with MS or CD under 18 years of age not established.
Elderly:
Studies did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.
Drug/lab interactions
Formal studies not completed. Concurrent use with antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infection, including PML and other opportunistic infections, over the risk observed with the use of natalizumab alone. Safety and efficacy of natalizumab in combination with any of these agents not established. ■ Concurrent use of short courses of corticosteroids was associated with an increase in infections in clinical trials. However, the increase in infections in both the natalizumab-treated and placebo-treated patients who received steroids was similar. Corticosteroids should be tapered in patients with CD who are initiating natalizumab therapy; see Usual Dose. ■ No data are available on the effects of vaccination in patients receiving natalizumab. ■ Increases circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. A return to baseline usually occurs within 16 weeks after the last dose. Elevations of neutrophils are not observed. ■ May induce mild decreases in hemoglobin, frequently transient.
Side effects
The most commonly reported adverse reactions were abdominal discomfort, arthralgia, depression, diarrhea, fatigue, gastroenteritis, headache, infections (UTI, upper and lower respiratory tract), nausea, pain in extremities, rash, and vaginitis. The most commonly reported serious adverse reactions were infections, hypersensitivity reactions (including anaphylaxis), depression (including suicidal ideation), and cholelithiasis. The most commonly reported adverse reactions resulting in clinical intervention (i.e., discontinuation of natalizumab) were urticaria and other hypersensitivity reactions. Infusion-related reactions (defined as any adverse event occurring within 2 hours of the start of an infusion) included headache, dizziness, fatigue, hypersensitivity reactions, nausea, pruritus, rigors, urticaria, and vomiting. Other reported adverse reactions included abnormal liver function tests, amenorrhea, antibody formation, chest discomfort, dermatitis, irregular menstruation/dysmenorrhea, local bleeding, muscle cramps, night sweats, pruritus, somnolence, syncope, tonsillitis, tremor, urinary urgency and frequency, and vertigo. Adverse reactions reported in persistently antibody-positive patients included anxiety, dyspnea, hypertension, myalgia, and tachycardia.
Post-marketing:
Eosinophilia (resolved with discontinuation of therapy), herpes simplex virus encephalitis and meningitis, herpes zoster virus meningitis, PML in patients treated with natalizumab monotherapy.
Antidote
Keep physician informed of all side effects. Most will be treated symptomatically. Discontinue natalizumab at the first sign of liver injury, S/S of meningitis or encephalitis, S/S suggestive of PML, or with any change in neurologic status. Discontinue infusion if any S/S of a hypersensitivity or infusion reaction occur. Treat with epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen as indicated. Patients who experience a hypersensitivity reaction should not be retreated with natalizumab.
Necitumumab 
(neh-CIT-ue-mew-mab)
Portrazza
Antineoplastic
(Monoclonal antibody, epidermal growth factor receptor [EGFR] inhibitor)
pH 6
Usual dose
Premedication:
For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), premedicate with diphenhydramine (Benadryl) or equivalent before all subsequent necitumumab infusions. For patients who have experienced a second occurrence of Grade 1or 2 IRR, premedicate before all subsequent necitumumab infusions with diphenhydramine (or equivalent), acetaminophen (or equivalent), and dexamethasone (Decadron) (or equivalent).
Necitumumab:
800 mg as an IV infusion over 60 minutes on Days 1 and 8 of each 3-week cycle. Administer before gemcitabine (Gemzar) and cisplatin infusions. Continue until disease progression or unacceptable toxicity. Refer to gemcitabine and cisplatin monographs for premedication, hydration, dose recommendations, precautions, monitoring, and other requirements before administration.
Dose adjustments
Reduce the infusion rate of necitumumab by 50% for a Grade 1 IRR. ■ Stop the infusion for a Grade 2 IRR. When signs and symptoms have resolved to Grade 0 or 1, resume necitumumab at a 50% reduced rate for all subsequent infusions. ■ Permanently discontinue necitumumab for a Grade 3 or 4 IRR. ■ Withhold necitumumab for Grade 3 dermatologic toxicity (e.g., rash or acneiform rash) until symptoms resolve to Grade 2 or less, then resume necitumumab at a reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, dose may be increased to 600 mg and 800 mg in subsequent cycles. ■ Permanently discontinue necitumumab for dermatologic toxicity if (1) the Grade 3 rash or acneiform rash does not resolve to Grade 2 or less within 6 weeks, (2) reactions worsen or become intolerable at a dose of 400 mg, (3) patient experiences a Grade 3 skin induration/fibrosis, or (4) patient experiences Grade 4 dermatologic toxicity. ■ Withhold necitumumab for Grade 3 or 4 electrolyte abnormalities. Administer subsequent cycles once electrolyte abnormalities have improved to Grade 2 or less. ■ No dose adjustment necessary based on body weight.
Dilution
Available as a preservative-free solution in a single-dose vial containing 800 mg/50 mL (16 mg/mL). Solution should be clear. Discard if discolored or particulate matter is present. Withdraw the desired dose and further dilute to a final volume of 250 mL with NS. Do not use solutions containing dextrose. Gently invert the container to ensure adequate mixing. Do not freeze or shake.
Filters:
Specific information not available.
Storage:
Before use, refrigerate at 2° to 8° C (36° to 46° F) in original carton to protect from light. Do not freeze or shake the vial. Diluted solution may be stored for no more than 24 hours if refrigerated or no more than 4 hours at RT. Discard any unused portion left in the vial.
Compatibility
Manufacturer states, “Do not dilute with solutions other than NS or co-infuse with other electrolytes or medication.” Use of a separate line required.
Rate of administration
Administer as an infusion over 60 minutes using an infusion pump through a separate infusion line. Flush the line with NS at the end of the infusion. Reduce rate or discontinue infusion for IRR; see Dose Adjustments.
Actions
A recombinant human IgG1 monoclonal antibody that specifically binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR internalization and degradation in vitro and also leads to antibody-dependent cellular cytotoxicity in EGFR-expressing cells. Elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days.
Indications and uses
First-line treatment of patients with metastatic squamous non–small-cell lung cancer in combination with gemcitabine and cisplatin.
Limitation of use:
Not indicated for treatment of nonsquamous non–small-cell lung cancer. These patients experienced more serious and fatal toxicities, including cardiopulmonary arrest/sudden death, within 30 days when administered necitumumab in combination with pemetrexed (Alimta) and cisplatin.
Contraindications
Manufacturer states, “None.”
Precautions
Administered by or under the direction of a physician specialist in a facility with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ■ Cardiopulmonary arrest and/or sudden death has been reported with necitumumab used in combination with gemcitabine and cisplatin. Some of these deaths occurred within 30 days of the last dose of necitumumab in patients with comorbid conditions, including a history of coronary artery disease, hypomagnesemia, COPD, and/or hypertension. ■ Hypomagnesemia occurred in most patients receiving necitumumab in combination with gemcitabine and cisplatin and was severe in 20% of patients. The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks after initiation of necitumumab. ■ Venous and arterial thromboembolic events (VTEs and ATEs), some fatal, have been observed. The most common VTEs were pulmonary embolism and deep vein thrombosis. The most common ATEs were cerebral stroke and ischemia and myocardial infarction. Risk is higher in patients with a reported history of VTEs or ATEs. ■ Dermatologic toxicities, some severe, have been reported. ■ Infusion-related reactions have been reported. Most IRRs occurred after the first or second administration of necitumumab; see Premedication and Monitor. ■ As with all therapeutic proteins, there is a potential for immunogenicity. ■ Renal function and mild to moderate hepatic impairment have no influence on the exposure to necitumumab based on population pharmacokinetic analysis; however, no formal studies have been conducted. No patients with severe hepatic impairment were enrolled in clinical trials.
Monitor:
Obtain serum electrolytes (including serum magnesium, potassium, and calcium), before each dose of necitumumab. Closely monitor for hypomagnesemia, hypocalcemia, and hypokalemia during treatment and for at least 8 weeks after the last dose is administered, with aggressive replacement when warranted during and after administration of necitumumab. ■ Withhold necitumumab for Grade 3 or 4 electrolyte abnormalities. ■ Monitor for S/S of venous and arterial thromboembolic events (e.g., chest pain, limb or abdominal swelling and/or pain, shortness of breath, loss of sensation or motor power, or altered consciousness, vision, or speech). ■ Monitor for dermatologic toxicities (e.g., acne, dermatitis acneiform, dry skin, erythema, generalized rash, maculopapular rash, rash, skin fissures). Usually develops within the first 2 weeks of therapy and resolves within 17 weeks after onset; see Dose Adjustments and Antidote. ■ Monitor for S/S of IRRs (e.g., chills, dyspnea, fever, hypotension, rash, tightness of the chest, urticaria, wheezing) during and after infusion; see Dose Adjustments and Antidote.
Patient education:
Blood levels of magnesium, potassium, and calcium may be decreased. Take medicines to replace these electrolytes exactly as advised by the physician. ■ Risk of venous and arterial thromboembolic events is increased. Promptly report chest pain, limb or abdominal swelling and/or pain, shortness of breath, loss of sensation or motor power, or altered consciousness, vision, or speech. ■ To reduce the risk of dermatologic reactions, minimize sun exposure with the use of protective clothing and sunscreen during treatment. ■ Immediately report S/S of an infusion-related reaction (e.g., breathing problems, chills, fever, rash, tightness of the chest, urticaria, wheezing). ■ There is a potential risk to a fetus and to postnatal development. Effective contraception is required in females of reproductive potential during treatment and for 3 months after the final dose. ■ See Maternal/Child.
Maternal/child:
Based on its mechanism of action, necitumumab can cause fetal harm or developmental anomalies. Effective contraception required; see Patient Education. ■ Discontinue breast-feeding during treatment and for 3 months after the final dose. ■ Safety and effectiveness for use in pediatric patients not established.
Elderly:
There was a higher incidence of venous thromboembolic events, including pulmonary embolism, in patients age 70 years and over compared with younger patients.
Drug/lab interactions
When used in combination with gemcitabine, the dose-normalized area under the curve (AUC) of gemcitabine was increased. Exposure to cisplatin was unchanged. Gemcitabine and cisplatin had no effect on the exposure of necitumumab.
Side effects
The most common adverse reactions (all grades) observed more frequently in patients treated with necitumumab than with gemcitabine and cisplatin alone were dermatitis acneiform, diarrhea, hypomagnesemia, rash, and vomiting. The most common severe (Grade 3 or higher) adverse events were thromboembolic events (including pulmonary embolism), rash, and vomiting. Acne, conjunctivitis, dry skin, electrolyte abnormalities (including hypocalcemia, hypokalemia, and hypophosphatemia), headache, hemoptysis, paronychia, pruritus, skin fissures, stomatitis, VTE, and weight decrease have been reported.
Antidote
Keep physician informed of all side effects. May constitute a medical emergency or will be treated symptomatically as indicated. Reduce the infusion rate of necitumumab by 50% for Grade 1 IRRs. Stop the infusion for Grade 2 IRRs. Treat infusion-related reactions as indicated and provide premedication (e.g., diphenhydramine [Benadryl], acetaminophen, corticosteroids) for subsequent infusions; see Usual Dose. When signs and symptoms have resolved to Grade 0 or 1, resume necitumumab at a 50% reduced rate for all subsequent infusions. Withhold necitumumab for Grade 3 or 4 electrolyte abnormalities. Permanently discontinue necitumumab for any of the following: (1) Grade 3 or 4 IRR, (2) Grade 3 rash or acneiform rash that does not resolve to Grade 2 or less within 6 weeks, (3) dermatologic reactions that worsen or become intolerable at a dose of 400 mg, (4) Grade 3 skin induration/fibrosis, or (5) Grade 4 dermatologic toxicity. See Dose Adjustments, Precautions, and Monitor.
Nelarabine 
(nell-ah-RA-ben)
Arranon
Antineoplastic
pH 5 to 7
Usual dose
1,500 mg/M2 administered as an infusion over 2 hours on Days 1, 3, and 5. Repeat every 21 days. The recommended duration of treatment has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression or until the patient experienced unacceptable toxicity, became a candidate for bone marrow transplant, or no longer continued to benefit from treatment.
Pediatric dose
650 mg/M2 administered as an infusion over 1 hour daily for 5 consecutive days. Repeat every 21 days; see Usual Dose.
Dose adjustments
Discontinue therapy for neurologic events of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater. Dosage may be delayed for other toxicity, including hematologic toxicity. ■ Has not been studied in patients with hepatic or renal impairment. Because nelarabine and ara-G are partially eliminated by the kidneys, clearance may be reduced in patients with renal insufficiency. No dose adjustment is recommended for patients with a CrCl equal to or greater than 50 mL/min. Dose recommendations are not available for patients with a CrCl less than 50 mL/min; see Precautions. ■ Use caution in dose selection for the elderly.
Dilution
Specific techniques required; see precautions.
Nelarabine is not diluted before administration. Available in a 250 mg/50 mL (5 mg/mL) vial. Transfer the appropriate dose into a polyvinylchloride (PVC) infusion bag or glass container and administer as an infusion. Example: An adult patient with a body surface area of 2 M2 would require a dose of 3,000 mg (1,500 mg/M2 × 2 M2 = 3,000 mg). 3,000 mg ÷ 250 mg/vial = 12 vials.
Filters:
Specific information not available.
Storage:
Store unopened vials at CRT. Stable in PVC infusion bags or glass containers for up to 8 hours at up to 30° C (86° F).
Compatibility
Specific information not available. Consider specific use; consult pharmacist.
Rate of administration
Adult dose:
A single dose evenly distributed over 2 hours.
Pediatric dose:
A single dose evenly distributed over 1 hour.
Actions
A prodrug of ara-G, a T-cell selective nucleoside metabolic inhibitor. Nelarabine is demethylated to ara-G and then converted through various metabolic processes to the active 5′-triphosphate, ara-GTP. Ara-GTP is incorporated into DNA, leading to inhibition of DNA synthesis and cell death. Nelarabine and ara-G are extensively distributed throughout the body and are rapidly eliminated from the plasma, with a mean half-life of 18 minutes and 3.2 hours, respectively. They are partially eliminated by the kidneys.
Indications and uses
Treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to treatment or has relapsed following treatment with at least two chemotherapy regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
Contraindications
Precautions
Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ For IV use only. ■ Administered by or under the direction of a physician specialist in a facility with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ■ Neurotoxicity is the dose-limiting toxicity. Severe neurologic events have been reported and may include altered mental states (e.g., coma, confusion, severe somnolence), central nervous system effects (e.g., ataxia, convulsions), and peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis. Events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome have also been reported. Full recovery from these events has not always occurred with cessation of therapy. ■ Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events. ■ Hematologic toxicity (e.g., anemia, leukopenia, neutropenia [including febrile neutropenia], thrombocytopenia) is common. ■ Use caution in patients with renal or hepatic impairment. Use has not been studied. Patients with a CrCl less than 50 mL/min or a bilirubin greater than 3 times the ULN may be at increased risk for toxicity. Monitor closely. ■ May develop tumor lysis syndrome. ■ See Drug/Lab Interactions.
Monitor:
Close monitoring for neurologic events is strongly recommended; see Precautions and Antidote. ■ Obtain a baseline CBC with platelets and monitor regularly. ■ Monitor renal and hepatic function (BUN, SCr, bilirubin). ■ Monitor for S/S of tumor lysis syndrome (e.g., hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, metabolic acidosis, urate crystalluria, and renal failure). ■ Adequate hydration, alkalinization of urine, and allopurinol are indicated to prevent and/or treat hyperuricemia due to tumor lysis syndrome. ■ Monitor for S/S of infection. Prophylactic antibiotics may be indicated pending results of C/S in a febrile neutropenic patient. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm3). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Avoid administration of live virus vaccines to immunocompromised patients.
Patient education:
Avoid pregnancy; nonhormonal birth control is recommended. ■ Use caution in tasks that require alertness. ■ Notify physician at first sign of infection or of new or worsening neurotoxicity (e.g., numbness, tingling, difficulty with fine motor coordination, unsteadiness, weakness, seizures).
Maternal/child:
Category D: avoid pregnancy; may cause fetal harm. ■ Discontinue breast-feeding. ■ The mean clearance of nelarabine is about 30% higher in pediatric patients than in adult patients. Half-lives of nelarabine and ara-G are shorter than those seen in adults—13 minutes and 2 hours, respectively.
Elderly:
May be at increased risk of neurologic adverse events. Clearance may be reduced in the elderly due to age-related renal impairment; see Dose Adjustments and Precautions.
Drug/lab interactions
Formal drug interaction studies have not been completed. ■ Concurrent administration with adenosine deaminase inhibitors (e.g., pentostatin [Nipent]) is not recommended; may decrease conversion of nelarabine to its active form and decrease its effectiveness. ■ Nelarabine and ara-G do not appear to inhibit the activities of human hepatic cytochrome P450 isoenzymes. ■ Fludarabine does not appear to affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP. ■ Do not administer live virus vaccines to immunocompromised patients receiving antineoplastic agents.
Side effects
Adults:
Side effects most frequently reported were anemia, constipation, cough, diarrhea, dizziness, dyspnea, fatigue, fever, headache, hyperuricemia, hypoesthesia, nausea, neutropenia, paresthesia, peripheral neurologic disorders, somnolence, thrombocytopenia, and vomiting. Other reported side effects included abdominal distension, abdominal pain, abnormal gait, anorexia, arthralgia, asthenia, back pain, blurred vision, chest pain, chills, confusion, dehydration, depression, edema, epistaxis, exertional dyspnea, extremity pain, febrile neutropenia, hyperglycemia, hypotension, increased AST, infection, insomnia, muscular weakness, myalgia, pain, peripheral edema, petechiae, pleural effusion, pneumonia, sinusitis, sinus tachycardia, stomatitis, and wheezing. Neurologic side effects in adults were mostly Grade 1 or 2 and included amnesia, ataxia, balance disorder, depressed level of consciousness, headache, hypoesthesia, neuropathy (peripheral, peripheral motor, and peripheral sensory), paresthesia, sensory loss, taste alteration, and tremor. Grade 3 events included aphasia, convulsion, hemiparesis, and loss of consciousness. Cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy also were reported. One patient had a cerebral hemorrhage (fatal), coma, and leukoencephalopathy.
Pediatric patients:
Side effects most frequently reported were anemia, decreased blood albumin and potassium levels, headache, increased transaminase levels, leukopenia, neutropenia, peripheral neurologic disorders, thrombocytopenia, and vomiting. Other reported side effects included asthenia; decreased calcium, glucose, and magnesium levels; increased bilirubin and SCr; and infection. Neurologic side effects that were greater than Grade 2 included ataxia, headache, hypertonia, hypoesthesia, motor dysfunction, neuropathy (peripheral, peripheral motor, and peripheral sensory), paralysis of the third and sixth nerves, paresthesia, seizures (convulsions, grand mal convulsions, status epilepticus), somnolence, tremor.
Overdose:
Myelosuppression, severe neurotoxicity (coma, paralysis), and potentially death.
Post-marketing:
Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome, increased blood creatine phosphokinase, opportunistic infections (fatal), rhabdomyolysis, tumor lysis syndrome.
Antidote
Notify physician of any side effects. Most will be treated symptomatically. Discontinue therapy for neurologic events of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater. Dosage may be delayed for other toxicity, including hematologic toxicity. Blood and blood products, antibiotics, and other adjunctive therapies must be available. 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. No known antidote; provide supportive care in overdose. Resuscitate as necessary.
Neostigmine methylsulfate
(nee-oh-STIG-meen METH-ill-SUL-fayt)
Bloxiverz
Acetylcholinesterase inhibitor
pH 5.5
Usual dose
Doses should be individualized. A peripheral nerve stimulator should be used to determine when neostigmine should be initiated and if additional doses are needed. Before neostigmine administration and up until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered before or concomitantly with neostigmine using a separate syringe.
Atropine:
0.6 to 1.2 mg IV for each 0.5 to 2 mg of neostigmine OR
Glycopyrrolate:
0.2 mg IV for each 1 mg of neostigmine; see Precautions.
Neostigmine:
0.03 to 0.07 mg/kg. This dose will generally achieve a train-of-four (TOF) twitch ratio of 90% within 10 to 20 minutes of administration. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the neuromuscular blocking agent (NMBA) being reversed, and whether there is a need to rapidly reverse the NMBA.
The 0.03 mg/kg dose is recommended for:
• Reversal of NMBAs with shorter half-lives (e.g., rocuronium) OR
• When the first twitch response to the train-of-four (TOF) stimulus is substantially greater than 10% of baseline or when a second twitch is present.
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