Usual dose

Administer peramivir within 2 days of onset of symptoms of influenza.

A single dose of 600 mg administered as an IV infusion over 15 to 30 minutes.

Dose adjustments

No dose adjustment is required in patients with a creatinine clearance of 50 mL/min or higher. ​■ ​Reduce dose in patients with a baseline creatinine clearance below 50 mL/min using the recommendations in the following chart.

■ No dose adjustment is required based on gender, impaired hepatic function, weight, or race (was evaluated primarily in Asians and Caucasians).

Dilution

Available in single-use vials containing 200 mg/ 20 mL (10 mg/mL) as a clear, colorless solution. Contains no preservatives. Do not use if seal over bottle opening is broken or missing. Calculate the number of vial(s) required for the recommended dose, and withdraw the required volume of peramivir and dilute by transferring into an IV bag or container of NS, ¹/₂NS, D5W, or LR to a maximum volume of 100 mL.

Compatibility

Compatible with NS, ¹/₂NS, D5W, or LR. Also compatible with materials commonly used for administration such as polyvinylchloride (PVC) bags and PVC-free bags, polypropylene syringes, and polyethylene tubing. Manufacturer states, “Do not mix or co-infuse with other intravenous medications.”

Rate of administration

A single dose as an infusion equally distributed over 15 to 30 minutes.

Actions

Peramivir is an antiviral drug with activity against the influenza virus. It is an inhibitor of the influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. The relationship between the antiviral activity in cell culture, the inhibitory activity in the neuraminidase assay, and the inhibition of influenza virus replication in humans has not been established. Maximum serum concentration is reached by the end of the infusion. In vitro binding to human plasma proteins is less than 30%. Not significantly metabolized in humans. Elimination half-life is approximately 20 hours. Primarily excreted as unchanged drug in urine.

Indications and uses

Treatment of acute uncomplicated influenza in patients 18 years or age and older who have been symptomatic for no more than 2 days.

Contraindications

Manufacturer states, “None.”

Precautions

Rare cases of serious skin and hypersensitivity reactions, including erythema multiforme, have been reported. ​■ ​Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as abnormal behavior, delirium, and hallucinations, which in some cases result in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but also can occur in uncomplicated influenza. Neuropsychiatric events (e.g., delirium and abnormal behavior) have been reported in patients with influenza who are receiving neuraminidase inhibitors, including peramivir. The contribution of peramivir to these events has not been established. ​■ ​There is no evidence for the efficacy of peramivir in any illness caused by agents other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Peramivir has not been shown to prevent such complications. ​■ ​Circulating seasonal influenza strains expressing neuraminidase resistance–associated substitutions have been observed in individuals who have not received peramivir. Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use peramivir. ​■ ​Has not been studied in patients with impaired hepatic function; however, because peramivir is cleared in urine by glomerular filtration, no clinically relevant problems are expected. ​■ ​Cross-resistance between peramivir (Rapivab), oseltamivir (Tamiflu), and zanamivir (Relenza) was observed in neuraminidase biochemical assays and cell culture assays. The clinical impact of this reduced susceptibility is unknown.

Drug/lab interactions

The concurrent use of peramivir with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. Because of the potential for interference between these two products, avoid the use of LAIV within 2 weeks before or 48 hours after administration of peramivir unless medically indicated. For LAIV, antiviral drugs may inhibit viral replication and may reduce vaccine efficacy. ​■ ​Inactivated influenza vaccine can be administered at any time. ​■ ​Not a substrate for CYP enzymes, does not affect glucuronidation, and is not a substrate or inhibitor of P-glycoprotein–mediated transport. ​■ ​No evidence of drug-drug interactions when peramivir was administered with oral rimantadine (Flumadine), oral oseltamivir (Tamiflu), or oral contraceptives containing ethinyl estradiol and levonorgestrel or when peramivir IM was administered with oral probenecid.

Side effects

The most common adverse reaction is diarrhea. Serious skin and hypersensitivity reactions and neuropsychiatric events have occurred. Constipation; decreased neutrophils; hypertension; increased ALT, AST, creatine phosphokinase, and serum glucose; and insomnia were also reported.

Antidote

Notify physician of any side effects. Discontinue the drug if indicated. Treat overdose with general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote. Treat hypersensitivity reactions as indicated (e.g., diphenhydramine [Benadryl], epinephrine [Adrenalin], albuterol) and resuscitate as necessary. Removed by hemodialysis.

Usual dose

Preassessment is required; see Monitor. Pertuzumab is given in combination with trastuzumab (Herceptin) and docetaxel (Taxotere). See docetaxel and trastuzumab monographs; preassessment and premedication indicated. Pertuzumab, trastuzumab, and docetaxel should be administered sequentially. Pertuzumab and trastuzumab can be given in any order. Docetaxel should be administered after pertuzumab and trastuzumab infusions are complete. An observation period of 30 to 60 minutes is recommended after each pertuzumab infusion and before beginning any subsequent infusion of trastuzumab or docetaxel.

Dose adjustments

If a dose is delayed or missed and the time between two infusions is less than 6 weeks, administer the 420-mg dose. Do not wait until the next planned dose. ■ If the time between two infusions is 6 weeks or more, readminister the initial dose of 840 mg and follow with the subsequent dose regimen of 420 mg beginning in 3 weeks. ■ Discontinue immediately for a serious hypersensitivity reaction. ■ Withhold pertuzumab and trastuzumab for at least 3 weeks if there is a drop in left ventricular ejection fraction (LVEF) to less than 45% or a LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values, and reassess LVEF in 3 weeks. Pertuzumab may be resumed if the LVEF recovers to greater than 49%, or if it recovers to between 45% and 49% if associated with less than a 10% absolute decrease below pretreatment values. If after a repeat assessment within approximately 3 weeks the LVEF has not improved or has declined further, pertuzumab and trastuzumab should be discontinued unless benefits outweigh risks for the individual patient. ■ Pertuzumab should be discontinued if trastuzumab treatment is discontinued. ■ Dose reductions are not recommended for pertuzumab. ■ See docetaxel monograph for docetaxel dose adjustments. ■ No dose adjustment is indicated in patients with mild or moderate renal impairment. In patients with severe renal impairment (CrCl less than 30 mL/min), no dose adjustments can be recommended because of the limited pharmacokinetic data available. ■ See Rate of Administration, Precautions, Monitor, and Antidote.

Dilution

Withdraw the calculated dose of pertuzumab from the vial(s) and inject into a 250-mL PVC or non-PVC polyolefin infusion bag of NS. Invert diluted solution gently to mix. Do not shake. Dilute only with NS. Do not use D5W. Immediate use is preferred.

Compatibility

Manufacturer states, “Do not mix pertuzumab with other drugs” and lists as incompatible with D5W.

Rate of administration

For IV infusion only; do not administer as an IV push or IV bolus. The rate of infusion may be slowed or interrupted if the patient develops an infusion-associated reaction. Discontinue immediately for a serious hypersensitivity reaction.

Actions

A recombinant humanized monoclonal antibody. It targets the human epidermal growth factor receptor 2 protein (HER2) and blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. By inhibiting specific pathways, cell growth arrest and apoptosis can occur. Pertuzumab also mediates antibody-dependent, cell-mediated cytotoxicity. Using pertuzumab alone inhibits the proliferation of human tumor cells, whereas the combination of pertuzumab and trastuzumab greatly augments antitumor activity in HER2-overexpressing xenograft models. Steady-state concentration can be reached after the first maintenance dose.

Indications and uses

Pertuzumab in combination with trastuzumab and docetaxel is indicated for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. ■ Pertuzumab in combination with trastuzumab and docetaxel is indicated for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathologic complete response rate. Data demonstrating improvement in event-free survival or overall survival is not available.

Contraindications

Known hypersensitivity to pertuzumab or to any of its excipients.

Precautions

For IV infusion only; do not administer as an IV push or IV bolus. ■ Assess HER2 status before beginning pertuzumab therapy. Testing should be done by a laboratory with demonstrated proficiency in the testing process using FDA-approved tests. In clinical studies, the only patients who have received benefit from pertuzumab therapy are those with HER2 protein overexpression. ■ Can cause fetal harm when administered to pregnant women; see Patient Education and Maternal/Child. ■ Administered by or under the direction of a physician specialist. ■ Adequate laboratory and supportive medical resources must be available. ■ Emergency equipment and drugs for treatment of left ventricular dysfunction and/or hypersensitivity or infusion reactions must be immediately available; see Antidote. ■ Can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients before and during treatment with pertuzumab. Decreases in LVEF with drugs that block HER2 activity, including pertuzumab, have been reported. Patients who have received prior anthracyclines or radiotherapy to the chest wall may be at higher risk for decreased LVEF. ■ Hypersensitivity reactions, including anaphylaxis, and infusion reactions have occurred. ■ Trastuzumab and docetaxel also have extensive precautions and monitoring requirements; a review of their monographs is imperative. ■ Effects on patients with severe renal impairment and/or hepatic impairment have not been studied. ■ A protein substance; has the potential for immunogenicity.

Drug/lab interactions

No formal drug interaction studies have been done. ■ No drug-to-drug interactions observed between pertuzumab and trastuzumab or between pertuzumab and docetaxel.

Side effects

The most common side effects when pertuzumab was administered in combination with trastuzumab and docetaxel were alopecia, diarrhea, fatigue, nausea, neutropenia, peripheral neuropathy, and rash. Anemia, thrombocytopenia, and vomiting were reported when carboplatin was added to the regimen. The most common Grade 3 and 4 adverse reactions were anemia, asthenia, diarrhea, fatigue, febrile neutropenia, leukopenia, neutropenia, and peripheral neuropathy. Adverse events occurring in 10% or more of patients treated with pertuzumab include arthralgia, constipation, decreased appetite, dizziness, dry skin, dysgeusia, dyspnea, headache, increased lacrimation, insomnia, itching, mucosal inflammation, myalgia, nail disorders, nasopharyngitis, stomatitis, upper respiratory tract infections, and vomiting. Clinically relevant adverse events reported in fewer than 10% of patients include left ventricular dysfunction (including symptomatic left ventricular systolic dysfunction), hypersensitivity and/or infusion reactions, paronychia, and pleural effusion. Adverse reactions were reported less frequently after discontinuation of docetaxel treatment.

Antidote

Notify physician of all side effects. Most will be treated symptomatically. If signs of an infusion reaction occur, slow or interrupt the infusion and treat appropriately. Monitor patients carefully until symptoms resolve. Discontinue immediately for a serious hypersensitivity reaction. Discontinue pertuzumab for a confirmed clinically significant decrease in left ventricular function. If treatment with pertuzumab and trastuzumab has been withheld because of a drop in LVEF and if LVEF has not improved or has declined further after a repeat assessment within approximately 3 weeks, pertuzumab and trastuzumab should be discontinued unless benefits outweigh risks for the individual patient. 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 from concurrent antineoplastics. Treat hypersensitivity reactions with epinephrine, antihistamines, corticosteroids, bronchodilators, and oxygen. Resuscitate as indicated.

Usual dose

Use only enough medication to achieve the desired effect. May take up to 15 minutes to reach peak levels in the brain; guard against overdose and excessive respiratory depression.

Pediatric dose

See comments under Usual Dose.

Neonatal dose

See comments under Usual Dose.

Dose adjustments

Reduce dose in impaired renal or hepatic function; usually required in the debilitated or elderly. ■ See Drug/Lab Interactions.

Dilution

Sterile powder must be slowly diluted with SWFI. Use a minimum of 3 mL of diluent. Also available in sterile vials and tubexes. Best if further diluted up to 10 mL with SWFI. Solutions from powder form must be freshly prepared. Use only absolutely clear solutions. Discard powder or solution exposed to air for 30 minutes.

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

60 mg (gr 1) or fraction thereof over 1 minute. Titrate slowly to desired effect. Rapid injection rate may cause symptoms of overdose (e.g., serious respiratory depression).

Actions

A sedative, hypnotic barbiturate of long duration with potent anticonvulsant effects. Phenobarbital is a CNS depressant. Onset of action is prompt by the IV route and becomes rapidly more intense. Effects last from 6 to 10 hours. Will effectively depress the motor cortex with small doses. Pain perception is unimpaired. Rapidly absorbed by all body tissues and excreted in changed form in the urine. Excreted more readily in alkaline urine. Crosses the placental barrier. Secreted in breast milk.

Indications and uses

Prolonged sedation (medical and psychiatric). ■ Anticonvulsant.

Contraindications

History of porphyria, impaired renal function, impaired hepatic function especially with any signs of hepatic coma, known hypersensitivity to barbiturates, previous addiction, severe respiratory depression including dyspnea, obstruction, or cor pulmonale.

Precautions

IV route usually reserved for critical situations. ■ Use caution in elderly and debilitated patients and those with asthma, pulmonary disease, shock, and impaired renal or hepatic function. ■ Status epilepticus can occur from too-rapid withdrawal. ■ May be habit forming. Use caution in acute or chronic pain. ■ Benzodiazepines (diazepam [Valium], midazolam [Versed]) generally preferred for sedation.

Drug/lab interactions

Use extreme caution if any other CNS depressants have been given, such as alcohol, aminoglycoside antibiotics, narcotic analgesics, anesthetics, antidepressants, antihistamines, hypnotics, MAO inhibitors, phenothiazines, sedatives, tranquilizers. Potentiation with respiratory depression may occur. ■ Inhibits effectiveness of corticosteroids, doxycycline, oral anticoagulants, oral contraceptives, propranolol, quinidine, and theophylline. Capable of innumerable interactions with many drugs. ■ May increase orthostatic hypotension with furosemide (Lasix). ■ Monitor phenytoin (Dilantin), felbamate (Felbatol), carbamazepine (Tegretol), valproic acid and phenobarbital levels when any combination of these drugs is used concurrently. ■ May decrease the pharmacologic effect of vitamin D. ■ May decrease plasma concentrations and effectiveness of triazole antifungals (e.g., itraconazole [Sporanox]).

Side effects

Rarely occur with slow injection of average doses.

Antidote

Notify the physician of any side effects. Symptomatic and supportive treatment is most important in overdose. Maintain an adequate airway with artificial ventilation if indicated. Keep the patient warm. IV volume expanders (dextran) and other IV fluids will help maintain adequate circulation. Diuretics may promote the elimination of the drug. Vasopressors (e.g., dopamine) will maintain BP.

Usual dose

Dose adjustments

Patients with liver cirrhosis (Child-Pugh Class B and Class C) may have decreased responsiveness to phenylephrine. Higher-end doses may be required to achieve BP goal. ■ Patients with end-stage renal disease may have increased responsiveness to phenylephrine. Initiate dosing at lower end of dosing range.

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 alpha-1 adrenergic receptor agonist. Interacts with the receptors on the vascular smooth muscle cells, resulting in vasoconstriction. Increases in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, and total peripheral vascular resistance are observed within minutes of administration. As blood pressure increases, vagal activity also increases, resulting in a reflex bradycardia. Active on most vascular beds, including renal, pulmonary, and splanchnic arteries. Duration of effect is 15 to 20 minutes. Terminal half-life is 2.5 hours. Metabolized primarily by monoamine oxidase and sulfotransferase. Excreted in urine, primarily as inactive metabolites.

Indications and uses

Treatment of clinically important hypotension resulting primarily from vasodilation in settings such as septic shock or anesthesia. (No longer recommended for routine use in treatment of hypotension related to septic shock.)

Contraindications

Hypersensitivity to phenylephrine or any of its components.

Precautions

Usually administered by or under the supervision of a physician knowledgeable in its use. ■ Intravascular volume depletion should be corrected. ■ Correct acidosis. Acidosis may reduce effectiveness of phenylephrine. ■ Because of its pressor effects, phenylephrine can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. ■ Avoid extravasation. Can cause necrosis or sloughing of tissue. ■ Can cause peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease. ■ Can cause severe bradycardia and decreased cardiac output. ■ Can increase the need for renal replacement therapy in patients with septic shock. ■ The pressor response to adrenergic drugs, including phenylephrine, can be increased in patients with autonomic dysfunction, such as may occur with spinal cord injuries. ■ Contains bisulfites; use caution in allergic individuals. ■ See Drug/Lab Interactions.

Drug/lab interactions

Oxytocic drugs (e.g., oxytocin) potentiate the increasing blood pressure effects of sympathomimetic pressor amines, including phenylephrine, with the potential for hemorrhagic stroke. ■ The pressor effect of phenylephrine is also increased in patients receiving MAO inhibitors (e.g., selegiline [Eldepryl]), tricyclic antidepressants (e.g., desipramine [Norpramin]), angiotensin, aldosterone, atropine, steroids (e.g., hydrocortisone), norepinephrine transporter inhibitors (e.g., atomoxetine), ergot alkaloids (e.g., methylergonovine maleate [Methergine]). ■ The pressor effect of phenylephrine is decreased in patients receiving alpha-adrenergic antagonists (e.g., doxazosin [Cardura], prazosin [Minipress]), phosphodiesterase type 5 inhibitors (e.g., sildenafil [Viagra]), mixed alpha- and beta-receptor antagonists (e.g., labetalol [Trandate], carvedilol [Coreg]), calcium channel blockers (e.g., diltiazem [Cardizem], nifedipine [Procardia]), benzodiazepines (e.g., diazepam [Valium], midazolam [Versed]), ACE inhibitors (e.g., enalapril [Vasotec], lisinopril [Zestril, Prinivil]), centrally acting sympatholytic agents (e.g., reserpine, guanfacine [Intuniv]).

Side effects

The most common side effects are headache, nausea, and vomiting. Other reported side effects include arrhythmias, blurred vision, chest pain, diaphoresis, dyspnea, epigastric pain, extravasation, fullness of head, hypersensitivity (sulfite sensitivity), hypertension, hypertensive crisis, ischemia, lower cardiac output, neck pain, nervousness, paresthesia, pruritus, pulmonary edema, rales, reflexive bradycardia, skin blanching, skin necrosis with extravasation, and tremor.

Antidote

To prevent sloughing and necrosis in areas of extravasation, with a fine hypodermic needle inject 5 to 10 mg of phentolamine (Regitine) diluted in 10 to 15 mL of NS liberally throughout the tissue in the extravasated area. Treatment should be started as soon as extravasation is recognized. Notify the physician of all side effects. IM injection may be preferable. Treat hypertension with phentolamine (Regitine). Treat cardiac arrhythmias as indicated. Treat bradycardia with atropine. Resuscitate as necessary.

Usual dose

In all situations, transfer to oral therapy 12 to 24 hours after a loading dose or as soon as practical. See Precautions and Monitor.

Pediatric dose

Dose adjustments

Use caution, lower dose, and slower rate of administration in the seriously ill, elderly, and cachectic patients. ■ Lower doses may also be required in patients with renal or hepatic disease or in those with hypoalbuminemia. Monitoring of unbound (free) phenytoin concentrations may be a better dosing guide. ■ See Drug/Lab Interactions.

Dilution

Available in 100- or 250-mg ampules or vials and in 100-mg syringes. After verifying patency, may be administered directly into a large peripheral or central vein through a large-gauge catheter. Alternately, may be further diluted in NS to a concentration of no less than 5 mg/mL and administered as an infusion. Use solution only when completely dissolved and clear.

Compatibility

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

Manufacturer recommends not adding to IV solutions other than NS or mixing with other medications and states that “the addition of phenytoin to dextrose or dextrose-containing solutions will result in precipitation.” Always flush line with NS before and after administration of any other drug through the same IV line. See Dilution.

One source suggests the following compatibilities:

Rate of administration

Because of the risk of local toxicity, IV phenytoin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Before administration, the patency of the IV should be tested with a sterile saline flush. Follow the administration of phenytoin with a saline flush to avoid local venous irritation due to the alkalinity of the solution.

Actions

A synthetic anticonvulsant, chemically related to barbiturates. Selectively stabilizes seizure threshold and depresses seizure activity in the motor cortex. Mechanism of action may be due to increasing efflux or decreasing influx of sodium ions across the cell membrane during generation of the action potential. Phenytoin reduces the maximum activity of the brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. Effective control in emergency treatment of seizures may take 15 to 20 minutes because of rate of injection required. Highly protein bound. Metabolized by cytochrome P₄₅₀ enzymes CYP2C9 and CYP2C19 and is excreted in changed form in the urine. Half-life ranges from 10 to 15 hours. Crosses the placental barrier. Secreted in breast milk.

Indications and uses

Control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures during neurosurgery. Parenteral phenytoin should be used only when oral phenytoin administration is not possible.

Contraindications

Known hypersensitivity to phenytoin or other hydantoin products. ■ Bradycardia; sinoatrial, second-, or third-degree heart block; Stokes-Adams syndrome. ■ Coadministration with delavirdine (Rescriptor).

Precautions

Discontinue immediately for hypersensitivity reactions; with caution, substitute a nonhydantoin anticonvulsant. When substituting a new anticonvulsant, consideration should be given to avoiding structurally related drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione). ■ Abrupt withdrawal may cause increased seizure activity. Gradually reduce dose, discontinue, or substitute alternative antiepileptic agents. ■ Not effective for absence seizures; combined therapy is required if both conditions are present. ■ Not indicated for seizures due to hypoglycemia or other metabolic causes. ■ Severe hypotension and cardiac arrhythmias have occurred with rapid infusion. Risk increases with increased rates, but adverse cardiac events have been reported at or below the recommended infusion rates. Careful cardiac monitoring is required during and after IV administration. Because of the risks of cardiac and local toxicity associated with IV phenytoin, oral phenytoin should be used whenever possible. ■ Use caution in hypotension and severe myocardial insufficiency. ■ Use caution with low serum albumin level, and adjust dose as indicated. Phenytoin is highly bound to serum protein (approximately 80% to 90% or more) and a reduced albumin causes an increase in free drug availability. ■ Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported. Usually presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Deaths have been reported. ■ Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported. Onset of symptoms is usually within 28 days but can occur later. ■ Discontinue phenytoin if skin rash appears unless the rash is clearly not drug related. ■ Selected patients of Asian ancestry (e.g., Han Chinese, Filipino, Malaysian, South Asian Indian, and Thai descent) with a specific human leukocyte antigen allele may have an increased risk of serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) from phenytoin therapy. ■ Cases of acute hepatotoxicity, including hepatic failure, have been reported. These events may be part of the spectrum of DRESS or may occur in isolation. Reactions have included elevated liver function tests, eosinophilia, fever, hepatomegaly, jaundice, leukocytosis, and lymphadenopathy. Discontinue immediately and substitute alternative anticonvulsant therapy. ■ Hematopoietic complications, some fatal, have been reported (e.g., agranulocytosis, granulocytopenia, leukopenia, thrombocytopenia, or pancytopenia with or without bone marrow suppression). ■ Some reports suggest a relationship between phenytoin and the development of lymphadenopathy (local or generalized). Lymph node involvement may occur with or without S/S resembling DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated, and alternative anticonvulsant therapy should be strongly considered. ■ Local toxicity, including purple glove syndrome (edema, discoloration, and pain distal to the injection site), has occurred and may or may not be associated with extravasation. Irritation may range from slight tenderness to extensive necrosis and sloughing. ■ Inhibits insulin release and may increase serum glucose; monitoring indicated in patients with diabetes. ■ Use with caution in patients with porphyria. Phenytoin may exacerbate this disease. ■ Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Some psychotic symptoms and/or behavioral changes resolved without intervention. Others required dose reduction or discontinuation of the antiepileptic agent.

Drug/lab interactions

Interactions are numerous and potentially life threatening. Review of drug profile by pharmacist imperative. ■ Coadministration with delavirdine (Rescriptor) is contraindicated. Has potential for loss of virologic response and possible resistance to delavirdine or to the class of nonnucleoside reverse transcriptase inhibitors. ■ Serum levels may be increased by alcohol (acute ingestion), amiodarone (Nexterone), antiepileptic agents (e.g., ethosuximide [Zarontin], felbamate [Felbatol], methsuximide [Celontin], oxcarbazepine [Trileptal], topiramate [Topamax]), azoles (e.g., fluconazole [Diflucan], itraconazole [Sporanox], ketoconazole [Nizoral], miconazole [Oravig], voriconazole [VFEND]), capecitabine (Xeloda), chloramphenicol (Chloromycetin), chlordiazepoxide (Librium), disulfiram (Antabuse), estrogens, fluorouracil (5-FU), fluoxetine (Prozac), fluvastatin (Lescol), fluvoxamine (Luvox), H₂ antagonists (e.g., cimetidine [Tagamet]), halothane, isoniazid (INH), methylphenidate (Ritalin), omeprazole (Prilosec), phenothiazines (e.g., prochlorperazine [Compazine]), salicylates (aspirin), sertraline (Zoloft), succinimides, sulfonamides (e.g., sulfadiazine, sulfamethoxazole/trimethoprim [Bactrim], sulfaphenazole), ticlopidine (Ticlid), tolbutamide (Orinase), trazodone (Desyrel), and warfarin (Coumadin). ■ Serum levels and effectiveness may be decreased by antineoplastics usually in combination (e.g., bleomycin [Blenoxane], carboplatin [Paraplatin], cisplatin, doxorubicin [Adriamycin], methotrexate), carbamazepine (Tegretol), chronic alcohol abuse, diazepam (Valium), diazoxide (Proglycem), folic acid, fosamprenavir (Lexiva), nelfinavir (Viracept), reserpine, rifampin (Rifadin), ritonavir (Norvir), St. John’s wort, theophylline, and vigabatrin (Sabril). ■ Phenytoin serum levels may be increased or decreased by phenobarbital (Luminal), valproate sodium (Depacon), and valproic acid (Depakene). Similarly, phenytoin may unpredictably affect the levels and efficacy of these drugs. ■ The addition of withdrawal of drugs while patients are undergoing phenytoin therapy may require an adjustment of the phenytoin dose. ■ Phenytoin will inhibit the effects of azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole [Noxafil], voriconazole), corticosteroids, doxycycline, estrogens, furosemide (Lasix), irinotecan (Camptosar), oral contraceptives, paclitaxel (Taxol), paroxetine (Paxil), quinidine, rifampin (Rifadin), sertraline (Zoloft), teniposide (Vumon), theophylline, and vitamin D. Dose adjustment of these agents may be indicated. ■ Phenytoin decreases plasma concentrations of active metabolites of albendazole (Albenza), HIV antivirals (e.g., efavirenz [Sustiva], lopinavir/ritonavir [Kaletra], indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir], saquinavir [Invirase]), antiepileptic agents (e.g., carbamazepine [Tegretol], felbamate [Felbatol], lamotrigine [Lamictal], oxcarbazepine [Trileptal], quetiapine [Seroquel], topiramate [Topomax]), atorvastatin (Lipitor), chlorpropamide (Diabinese), clozapine (Clozaril), cyclosporine (Sandimmune), digoxin (Lanoxin), fluvastatin (Lescol), folic acid, methadone (Dolophine), mexiletine, nifedipine (Procardia), nimodipine, nisoldipine (Sular), praziquantel (Biltricide), simvastatin (Zocor), and verapamil. Adjust doses of these agents as indicated. ■ Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir (Agenerase), the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir (Agenerase). ■ May increase or decrease PT/INR responses when coadministered with warfarin (Coumadin). ■ Chronically administered phenytoin may cause resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents (e.g., cisatracurium [Nimbex], pancuronium, rocuronium [Zemuron], and vecuronium). Monitor patients closely; recovery from neuromuscular blockade may be more rapid than expected, and infusion rate requirements may be higher. ■ Alters some clinical laboratory tests (e.g., may decrease T₄; may increase glucose, alkaline phosphatase, and GGT; and may produce low results in dexamethasone or metyrapone tests).

Side effects

Altered tatste sensation, ataxia, confusion, constipation, decreased coordination, dizziness, drowsiness, dyskinesias, fever, headache, hyperplasia of gums, insomnia, nausea, nervousness, nystagmus, paresthesia, skin eruptions, slurred speech, somnolence, tremors, vertigo, visual disturbances, vomiting.

Antidote

Notify the physician of any side effects. If minor symptoms progress or any major side effect occurs, discontinue the drug and notify the physician; see Precautions. Maintain a patent airway and resuscitate as necessary. Symptoms of heart block or bradycardia may be reversed with IV atropine. Epinephrine may also be useful. Decrease rate or discontinue infusion for severe hypotension or cardiac arrhythmias. Hemodialysis may be useful in overdose.

Usual dose

Dependent on individual needs of the patient.

Infant dose

Dose adjustments

Lower-end initial doses may be indicated in the elderly based on the potential for decreased organ function and concomitant disease or drug therapy.

Dilution

Must be diluted in a larger volume of suitable IV solution and given as an infusion. Soluble in most commonly used IV solutions (see chart on inside back cover) except protein hydrolysate. Mix thoroughly. See Compatibility.

Compatibility (underline indicates conflicting compatibility information)

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

Rate of administration

A usual dose is usually equally distributed over 6 hours. Other sources suggest administering up to 15 mM over 2 hours, up to 30 mM over 4 hours, and up to 45 mM over 6 hours. Potassium phosphate will be further limited by the maximum rate for potassium. Consider sodium/potassium content. Infuse slowly. Rapid infusion may cause phosphate or potassium intoxication. Serum calcium may be reduced rapidly, causing hypocalcemic tetany.

Actions

Involved in bone deposition. Helps to maintain calcium levels, has a buffering effect on acid-base equilibrium, and influences renal excretion of the hydrogen ion. Normal levels in adults, 3 to 4.5 mg/dL of serum; in pediatric patients, 4 to 7 mg/dL. Excreted in urine.

Indications and uses

To prevent or correct hypophosphatemia in patients with restricted or no oral intake.

Contraindications

Any disease with high phosphate or low calcium levels, hyperkalemia (potassium phosphate), hypernatremia (sodium phosphate).

Precautions

Rapid infusion may cause phosphate, sodium, or potassium intoxication. Serum calcium may be reduced, rapidly causing hypocalcemic tetany. ■ Use sodium phosphate with caution in renal impairment, cirrhosis, cardiac failure, or any edematous, sodium-retaining state. ■ Use potassium phosphate with caution in cardiac disease, renal disease, and digitalized patients. ■ See Compatibility.

Drug/lab interactions

May cause hyperkalemia with potassium-sparing diuretics (e.g., amiloride) or angiotensin-converting enzyme inhibitors (e.g., enalapril [Vasotec]).

Side effects

Elevated phosphates, reduced calcium levels and hypocalcemic tetany, elevated potassium levels causing cardiac arrhythmias, flaccid paralysis, heaviness of the legs, hypotension, listlessness, mental confusion, paresthesia of the extremities.

Antidote

For any side effect, discontinue the drug and notify the physician. Restore serum calcium with calcium gluconate or chloride. Shift potassium from serum to cells with 150 mL of ¹/₆ M sodium lactate or 10% to 20% dextrose with 10 units regular insulin for each 20 Gm dextrose at 300 to 500 mL/hr. Correct acidosis with sodium bicarbonate. Reduce sodium by restriction, diuretics, or hemodialysis. Resuscitate as necessary.

Usual dose

Pediatric dose

To be used in life-threatening situations only. 0.02 mg/kg/dose. May be repeated at 5- to 10-minute intervals only if toxic effects persist and there is no sign of cholinergic effects. Maximum total dose is 2 mg. See Maternal/Child.

Dilution

May be given undiluted. Do not add to IV solutions. May be given through Y-tube or three-way stopcock of infusion set.

Compatibility

Specific information not available. Consider specific use; consult pharmacist.

Rate of administration

Rapid IV administration may cause bradycardia, hypersalivation, respiratory distress, and convulsions.

1 mg or fraction thereof over 1 to 3 minutes.

Actions

An extract of Physostigma venenosum seeds. It inhibits the destructive action of acetylcholinesterase and prolongs and exaggerates the effects of acetylcholine. Stimulates parasympathetic nerve stimulation (pupil contraction, increased intestinal musculature tonus, bronchial constriction, salivary and sweat gland stimulation). Does enter the CNS. Onset of action occurs in 5 minutes and lasts about 1 hour. Rapidly hydrolyzed by cholinesterases.

Indications and uses

To reverse CNS toxic effects caused by drugs capable of producing anticholinergic poisoning (e.g., atropine), other anticholinergic/antispasmodic agents (e.g., phenothiazines, antihistamines), anticholinergic antiparkinson agents (e.g., benztropine [Cogentin], trihexyphenidyl [Artane]), and tricyclic antidepressants (e.g., imipramine [Tofranil]).

Contraindications

Asthma, cardiovascular disease, diabetes, gangrene, mechanical obstruction of the intestines or urogenital tract, vagotonic states, patients receiving choline esters, depolarizing neuromuscular blocking agents (succinylcholine), or tricyclic antidepressants (e.g., amitriptyline [Elavil]).

Precautions

Rapid IV administration may cause bradycardia, hypersalivation, respiratory distress, and convulsions. ■ Contains bisulfites; use caution in allergic individuals.

Drug/lab interactions

Potentiates succinylcholine and other choline esters (e.g., bethanecol). ■ May antagonize CNS depressant effects of diazepam (Valium). ■ May cause serious complications, including death, with tricyclic antidepressants (e.g., amitriptyline [Elavil]).

Side effects

Anxiety, bradycardia, cholinergic crisis (overdose), coma, convulsions, defecation, delirium, disorientation, emesis, hallucinations, hyperactivity, hypersalivation, hypersensitivity, nausea, respiratory distress, salivation, seizures, sweating, urination.

Antidote

Keep physician informed of side effects. For excessive nausea or sweating, reduce dose. Discontinue drug for bradycardia; convulsions; excessive defecation, emesis, salivation, or urination; or respiratory distress. Treat cholinergic side effects (e.g., arrhythmias, bronchoconstriction) or hypersensitivity with the specific antagonist atropine sulfate in doses of 0.6 mg IV. May be repeated every 3 to 10 minutes. Endotracheal intubation or tracheostomy are considered prophylactic in anesthesia or crisis. Artificial ventilation, oxygen therapy, cardiac monitoring, adequate suctioning, and treatment of shock or convulsions must be instituted and maintained as necessary.

Usual dose

Should be given by the SC or oral route whenever possible; parenteral route administration has caused death; see Precautions. A single dose is preferred, but it may be repeated if clinically indicated.

Pediatric dose

See Usual Dose, Precautions, and Maternal/Child.

Newborn dose

See Usual Dose, Precautions, and Maternal/Child. Rarely given IV in the newborn. SC injection preferred.

Dose adjustments

See Drug/Lab Interactions.

Dilution

Use only preservative-free solutions. May be diluted only with NS, D5NS, or D5W. Dilution with at least 10 mL of diluent is recommended to facilitate prescribed rate of administration. Photosensitive; protect from light in all dilutions. Use immediately after preparation.

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

Each 1 mg or fraction thereof over 1 minute or longer. Too-rapid injection has caused severe reactions, including fatalities.

Actions

Vitamin K, a fat-soluble vitamin, is essential for hepatic production of four blood coagulation factors including prothrombin. These are required for normal blood clotting. Onset of action is within 1 to 2 hours. Usually controls hemorrhage in 3 to 6 hours; normal prothrombin levels should be obtained in 12 to 14 hours. Metabolized by the liver and eliminated in urine and bile.

Indications and uses

Coagulation disorders due to faulty formation of factors II, VII, IX, and X when caused by vitamin K deficiency or interference with vitamin K activity. Indicated in anticoagulant-induced prothrombin deficiency (warfarin or dicumarol). ■ Prophylaxis and treatment of hemorrhagic disease of the newborn. ■ Hypoprothrombinemia resulting from antibacterial therapy. ■ Hypoprothrombinemia secondary to factors limiting the absorption or synthesis of vitamin K (e.g., obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, and regional enteritis). ■ Other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism (e.g., salicylates).

Contraindications

Hypersensitivity to components.

Precautions

IV and/or IM is not the route of choice; used only when SC or oral route cannot be used. Use extreme caution; has caused severe reactions, including death, with the first injection, even when the product has been diluted and infused slowly. ■ As an alternative to administering phytonadione, discontinuation or reduction of the doses of drugs interfering with coagulation mechanisms (e.g., antibiotics, salicylates) should be considered. The severity of the coagulation disorder should determine if phytonadione is required in addition to discontinuing or reducing the doses of interfering drugs. To correct excess anticoagulation after the use of warfarin (Coumadin) (e.g., returning an increased INR to the desired range), consider the degree of elevation and the presence of clinically significant bleeding. ■ Supplement with whole blood transfusion or blood components if indicated. ■ Now the only vitamin K product for IV use. ■ Do not use to counteract anticoagulant effects of heparin; not effective. Protamine sulfate is indicated. ■ Does not restore abnormal platelet function to normal. ■ Does not correct hypoprothrombinemia due to hepatocellular damage. ■ When phytonadione is used in a patient for whom anticoagulant therapy is indicated, the same clotting hazards that existed before beginning anticoagulant therapy will recur. Use the smallest dose of phytonadione possible and monitor PT.

Drug/lab interactions

Discontinue drugs adversely affecting the coagulation mechanism if possible (e.g., salicylates, antibiotics). ■ May cause temporary resistance to prothrombin-depressing oral anticoagulants by increasing amount of phytonadione in the liver and blood. Anticoagulation will require larger doses of same or use of heparin sodium.

Side effects

Cyanosis, diaphoresis, dizziness, dyspnea, hyperbilirubinemia, hypotension, injection site reactions, peculiar taste sensations, rapid and weak pulse, tachycardia, transient flushing sensation. Anaphylaxis, cardiac and/or respiratory arrest, shock, and death have occurred with parenteral route.

Antidote

Should not be necessary if dosage is accurately calculated before administration. Action can be reversed by warfarin or heparin if indicated. Discontinue the drug and notify the physician of any side effects. For most side effects the physician will probably choose to continue the drug at a decreased rate of administration. Treat hypersensitivity reactions as necessary.

Usual dose

Measurement of both drugs is included in the total dose; for every 1 Gm of piperacillin there is 0.125 Gm of tazobactam (8:1 ratio).

12 Gm piperacillin/1.5 Gm tazobactam/24 hours given as 3.375 (3 Gm piperacillin/0.375 Gm tazobactam) every 6 hours. Usual duration of therapy is 7 to 10 days, based on severity of infection and patient progress.

Pediatric dose

Dose adjustments

No dose adjustment needed in impaired liver function. ■ Dose reduction may be required in the elderly. ■ Adjust dose in adult patients with impaired renal function based on the following chart. ■ Dose recommendations for pediatric patients with impaired renal function are not available.

Piperacillin/Tazobactam Dose Guidelines in Adults with Impaired Renal Function
Renal Function (Creatinine Clearance, mL/min)	All Indications (Except Nosocomial Pneumonia)	Nosocomial Pneumonia
>40 mL/min	3.375 Gm q 6 hr	4.5 Gm q 6 hr
20-40 mL/min*	2.25 Gm q 6 hr	3.375 Gm q 6 hr
<20 mL/min*	2.25 Gm q 8 hr	2.25 Gm q 6 hr
Hemodialysis†	2.25 Gm q 12 hr	2.25 Gm q 8 hr
CAPD	2.25 Gm q 12 hr	2.25 Gm q 8 hr

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