Usual dose

Prehydration required; see Precautions and Monitor. See Dose Adjustments. May be given in combination with amifostine (Ethyol) to reduce nephrotoxicity and neurotoxicity of cisplatin. See amifostine monograph. Administration as a 6- to 8-hour infusion with intravenous hydration and mannitol has been used to reduce nephrotoxicity. Doses greater than 100 mg/M² once every 3 to 4 weeks are rarely used.

Dose adjustments

All doses adjusted based on prior radiation therapy or chemotherapy. ■ Repeat doses may not be given unless SCr is below 1.5 mg/100 mL and/or BUN is below 25 mg/100 mL. Renal toxicity becomes more prolonged and severe with repeated courses. Renal function must return to normal before next dose is given. ■ Platelets should be 100,000/mm³ and leukocytes 4,000/mm³; verify auditory acuity as within normal limits. ■ Dosing should be cautious in the elderly. Lower-end initial doses may be indicated. Consider decrease in cardiac, hepatic, and renal function; concomitant disease; or other drug therapy; see Elderly.

Dilution

Compatibility (underline indicates conflicting compatibility information)

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

Manufacturer states, “Do not use needles, IV sets, or equipment containing aluminum.” Aluminum reacts with cisplatin, causing precipitate formation and loss of potency. A precipitate will form if reconstituted solutions are refrigerated.

One source suggests the following compatibilities:

Rate of administration

Administer as a slow IV infusion; should not be given as a rapid IV injection. Rates vary based on protocol. Manufacturer suggests administering each 1 liter of infusion solution over 3 to 4 hours. Give total dose (2 liters) over 6 to 8 hours. Rate must be sufficient to maintain hydration and diuresis. Infusion times of 30 to 120 minutes are common, but infusion time has also been extended to 24 hours/dose. One source recommends a maximum rate not to exceed 1 mg/min. Too-rapid administration increases nephrotoxicity and ototoxicity.

Actions

A heavy metal complex (platinum and chloride atoms). Has properties similar to alkylating agents and is cell-cycle nonspecific. Inhibits DNA synthesis by formation of DNA cross-links. Concentration is highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen. Heavily protein bound. Only one fourth to one half of the drug is excreted in the urine by the end of 5 days. Platinum may be present in tissues for as long as 180 days after the last administration. Secreted in breast milk.

Indications and uses

Treatment of metastatic testicular tumors; used in combination therapy with other approved chemotherapy agents in patients who have already received appropriate surgical and/or radiotherapeutic procedures. ■ Treatment of metastatic ovarian tumors; used in combination therapy with other approved chemotherapy agents in patients who have already received appropriate surgical and/or radiotherapeutic procedures. ■ Used as a single agent as secondary treatment in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy. ■ Used as a single agent for treatment of patients with transitional cell bladder cancer that is no longer amenable to local treatment such as surgery and/or radiotherapy. ■ Is used in specific combinations with other chemotherapeutic drugs.

Contraindications

Hypersensitivity to cisplatin or other platinum-containing compounds, myelosuppressed patients, pre-existing impaired renal function, or hearing deficit.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist. ■ Adequate facilities and emergency resuscitation equipment and supplies must always be available. ■ Renal toxicity can be cumulative and may be severe. ■ Other major dose-related toxicities include myelosuppression, nausea, and vomiting. ■ Ototoxicity (tinnitus, loss of high-frequency hearing, and/or deafness) can be significant and may be more pronounced in pediatric patients. ■ Anaphylaxis has been reported and may occur within minutes of cisplatin administration. ■ Labeling changed to read, “Doses greater than 100 mg/M²/cycle once every 3 to 4 weeks are rarely used.” This is an effort to eliminate serious errors resulting from confusion with carboplatin (Paraplatin). Flip-off seal on vial now says, “Call Dr. if dose greater than 100 mg/M²/cycle.” ■ Neuropathies may occur with higher doses, greater frequency of average doses, or prolonged therapy. Usually occur after prolonged therapy but have been reported after a single dose. If symptoms of neuropathy are observed, discontinue cisplatin. ■ See Elderly.

Drug/lab interactions

Ototoxicity and nephrotoxicity are potentiated with other ototoxic or nephrotoxic agents (e.g., aminoglycosides [e.g., gentamicin] and loop diuretics [e.g., furosemide (Lasix), ethacrynic acid (Edecrin)]). Concurrent use not recommended (Lasix is used to control fluid overload; use caution). ■ Serum levels of anticonvulsant agents (e.g., phenytoin [Dilantin]) may become subtherapeutic when used concurrently with cisplatin. Monitor anticonvulsant levels; increased doses may be indicated. ■ Bone marrow toxicity increased with other antineoplastic agents and/or radiation therapy. ■ Synergistic with etoposide (VePesid); may be beneficial. ■ May affect renal excretion and increase toxicity of many drugs (e.g., bleomycin, methotrexate). ■ Response duration may be shortened with concurrent use of pyridoxine (vitamin B₆) and altretamine (Hexalen). ■ Do not administer live virus vaccines to patients receiving antineoplastic agents.

Side effects

Are frequent; can occur with the initial dose and will become more severe with succeeding doses. Dose-related and cumulative renal insufficiency, including renal failure, is the major dose-limiting toxicity (often noted during the second week following a dose). Acute leukemia, alopecia, anaphylaxis (facial edema, hypotension, tachycardia, and wheezing within minutes of administration), asthenia, cardiac abnormalities, dehydration, diarrhea, electrolyte disturbances (hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia), elevated serum amylase, hemolytic anemia, hepatotoxicity, hyperuricemia, malaise, myelosuppression, nausea and vomiting (acute or delayed), syndrome of inappropriate antidiuretic hormone (SIADH), neurotoxicity (including peripheral neuropathy that may be reversible, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome [RPLS]), ocular toxicity (e.g., blurred vision, cerebral blindness, optic neuritis, papilledema), ototoxicity including tinnitus and hearing loss in the high-frequency range, peripheral neuropathy (may be irreversible), vascular toxicities (e.g., cerebral arteritis, CVA, MI, or thrombotic microangiopathy [hemolytic-uremic syndrome (HUS)]), and vestibular toxicity.

Antidote

Notify physician of all side effects. Cisplatin may have to be discontinued permanently or until recovery. Symptomatic and supportive treatment is indicated. 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. Pretreatment with amifostine may reduce nephrotoxic, neurotoxic, and hematologic effects. Treat anaphylaxis with epinephrine, corticosteroids, oxygen, and antihistamines. There is no specific antidote. Hemodialysis appears to have little effect on removing platinum from the body because of the rapid and high degree of protein binding.

Usual dose

In all situations, may be administered on an outpatient basis with an appropriate pump and a central venous line in place. Administer any subsequent course with extreme caution. Hematologic recovery must be considered.

Dose adjustments

May be required with severe bone marrow impairment, with prior radiation or myelosuppressive agents. ■ May be required in severe renal insufficiency; effects of renal or hepatic impairment on excretion of cladribine not yet clarified for humans. ■ See Drug/Lab Interactions.

Dilution

Compatibility

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

D5W will cause degradation of cladribine. Manufacturer states, “Adherence to the recommended diluents and infusion systems is advised.”

One source suggests the following compatibilities:

Rate of administration

Actions

A chlorinated purine nucleoside analog and synthetic antineoplastic agent. Mechanism of action is not known, but it is believed to be cytotoxic by inhibiting both DNA synthesis and repair. Affects both dividing and resting cells. The 7-day course for hairy cell leukemia has resulted in complete response in a majority of patients with no evidence of persistent bone marrow disease. Crosses the blood-brain barrier. Average half-life is 4.2 to 9.2 hours. Specific methods of metabolism and routes of excretion are not known. Some drug does appear in urine.

Indications and uses

Treatment of active hairy cell leukemia (HCL) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.

Contraindications

Hypersensitivity to cladribine or any of its components; neonates (7-day dilution contains benzyl alcohol).

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist. ■ Anticipate severe suppression of bone marrow function, including neutropenia, anemia, and thrombocytopenia; usually reversible and appears to be dose dependent. ■ Myelosuppressive effects are most notable during the first month after therapy. ■ Serious, sometimes fatal, infections have been reported (e.g., respiratory tract infections, pneumonia, viral skin infections, sepsis). ■ Neurologic toxicity, including paraparesis and quadriparesis, has been reported. Usually occurs with higher doses but has been seen with standard dosing regimens. ■ Because of the possibility of increased toxicity, use caution in known or suspected renal or hepatic insufficiency, or any severe bone marrow impairment, or prior cytoxic or radiation therapy. ■ Acute nephrotoxicity has been observed with high doses (4 to 9 times the recommended dose for HCL). Risk of toxicity increased when given concurrently with other nephrotoxic agents and/or therapies. ■ Rare cases of tumor lysis syndrome have been reported. ■ Appears to be no relationship between serum concentrations and ultimate clinical outcome. ■ Additional courses did not improve overall response. ■ Current studies suggest that overall response rate may be decreased in patients previously treated with splenectomy, deoxycoformycin (pentostatin), and in patients refractory to alpha-interferon. ■ May cause prolonged bone marrow hypocellularity; clinical significance not known.

Drug/lab interactions

Increased toxicity with other myelosuppressive agents (e.g., methotrexate). ■ May raise concentration of blood uric acid; increased doses of antigout agents (e.g., allopurinol [Aloprim]) may be indicated; avoid uricosurics (e.g., probenecid, sulfinpyrazone [Anturane]). ■ Do not administer live attenuated vaccines to patients receiving antineoplastic agents.

Side effects

Fever occurs first. Onset of thrombocytopenia begins in 7 to 10 days followed by anemia (severe) and neutropenia (severe). Fatigue, headache, injection site reactions, infection, nausea, and rash are common. Many other side effects may or may not be related to cladribine: abdominal pain, abnormal breath sounds, abnormal chest sounds, anorexia, arthralgia, asthenia, chills, constipation, cough, diaphoresis, diarrhea, dizziness, edema, epistaxis, erythema, insomnia, malaise, myalgia, pain, petechiae, pruritus, purpura, shortness of breath, tachycardia, trunk pain, weakness, vomiting.

Antidote

Keep physician informed of all side effects; many will be treated symptomatically as indicated. Platelet or RBC transfusions are frequently required to treat anemia or thrombocytopenia, especially during the first month. Filgrastim (Neupogen, Zarxio) or pegfilgrastim (Neulasta) may be used to increase neutrophil count, although recovery is usually spontaneous. Use specific antibiotics to combat infection. Discontinue cladribine if renal toxicity, neurotoxicity, or overdose occurs. No specific antidote for overdose. Supportive therapy as indicated will help sustain the patient in toxicity. Resuscitate if indicated.

Usual dose

Must be individualized to achieve the desired BP reduction. Titrate to patient response and BP goal.

Dose adjustments

Lower-end initial doses may be indicated in the elderly. Consider the potential for decreased organ function and concomitant disease or drug therapy. ■ Patients with abnormal hepatic or renal function may receive the initial dose listed under Usual Dose.

Dilution

Strict aseptic technique is imperative. Available as a single-dose, ready-to-use vial containing a 0.5-mg/mL phospholipid emulsion that can support microbial growth. Invert vial gently several times before use to ensure uniformity of emulsion.

Compatibility

Manufacturer states, “Should not be administered in the same line as other medications. Should not be diluted, but can be administered via a Y-tube or medication port with SWFI, NS, D5W, D5NS, D5LR, LR, and 10% amino acid.”

Rate of administration

Administer as a continuous infusion as outlined in Usual Dose. Use of an infusion device required. May be given through a central or peripheral line.

Actions

A dihydropyridine calcium channel blocker. Mediates the influx of calcium during depolarization in arterial smooth muscle. Reduces mean arterial BP by decreasing systemic vascular resistance in a dose-dependent manner. Does not reduce cardiac filling pressure (preload), confirming the lack of effect on venous capacitance vessels. Vasodilation and the resulting decrease in BP may produce a reflex increase in heart rate. Onset of effects begins within 2 to 4 minutes. Evidence of tolerance or hysteresis has not been observed in patients receiving infusions of up to 72 hours’ duration. Full recovery of BP is achieved 5 to 15 minutes after the infusion is stopped. Rapidly distributed. Highly protein bound. Metabolized by hydrolysis in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. Half-life is approximately 15 minutes. Excreted primarily in urine and, to a lesser extent, in feces.

Indications and uses

Reduction of BP when oral therapy is not feasible or not desirable.

Contraindications

Allergies to soybeans, soy products, eggs, or egg products. ■ Defective lipid metabolism such as pathologic hyperlipidemia, lipoid nephrosis, or acute pancreatitis if accompanied by hyperlipidemia. ■ Severe aortic stenosis (afterload reduction can be expected to reduce myocardial oxygen delivery).

Precautions

For IV use only. ■ Strict aseptic technique required; see Dilution. ■ May produce systemic hypotension and reflex tachycardia. Dose reduction may be indicated. ■ Use caution in patients with lipid metabolism disorders. Contains approximately 0.2 Gm of lipid per mL. Lipid intake restrictions may be necessary in these patients. A reduction in the quantity of concurrently administered lipids (e.g., propofol, IV fat) may be necessary to compensate for the amount of lipid infused as part of the clevidipine formulation. See Usual Dose. ■ May produce a negative inotropic effect and exacerbate heart failure. ■ Rebound hypertension may occur in patients undergoing prolonged therapy; see Monitor. ■ Has not been studied for the treatment of hypertension associated with pheochromocytoma.

Drug/lab interactions

Formal studies have not been conducted. ■ Does not have the potential for inducing or inhibiting the cytochrome P₄₅₀ system. ■ Use of beta-blockers as treatment for clevidipine-induced reflex tachycardia is not recommended. Experience is limited. ■ If used concomitantly with beta-blockers and beta-blockers are to be discontinued, withdraw beta-blocker therapy gradually. Clevidipine will not protect against the effects of abrupt beta-blocker withdrawal.

Side effects

Acute renal failure, atrial fibrillation, cardiac arrest, dyspnea, flushing, headache, hypotension, myocardial infarction, nausea, peripheral edema, rebound hypertension, reflex tachycardia, syncope, and vomiting.

Antidote

Notify physician of any side effects; most will be treated symptomatically. Reduce dose for systemic hypotension or reflex tachycardia. Discontinue for suspected overdose. Reduction in antihypertensive effects should be seen within 5 to 15 minutes. Monitor BP and support if needed. Resuscitate as necessary.

Usual dose

Doses based on susceptibility of specific organisms; see literature.

Pediatric dose

Neonatal dose

See Maternal/Child.

Dose adjustments

Dose adjustments are not required in the presence of mild to moderate renal or hepatic disease and should not be required in severe disease; see Monitor.

Dilution

Available prediluted in 300-, 600-, and 900-mg doses, in ADD-Vantage vials for use with ADD-Vantage infusion containers, as a 150 mg/mL solution in flip-top vials, in ready-to-use Galaxy bags, and in pharmacy bulk packages (for use only by the pharmacy). Dilute ADD-Vantage vials with 50 to 100 mL of D5W or NS. Doses prepared using the 150 mg/mL solutions are most commonly diluted in 50 to 100 mL of D5W, NS, or other compatible infusion solution. Concentration of clindamycin in diluent should not exceed 18 mg/mL. See chart on inside back cover or product insert for additional diluents. May be further diluted in larger amounts of compatible infusion solutions and given as a continuous infusion after the initial dose.

Compatibility (underline indicates conflicting compatibility information)

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

Manufacturer lists as compatible for 24 hours at RT with IV solutions containing sodium chloride, glucose, calcium, or potassium and with solutions containing vitamin B complex in concentrations usually used clinically. Manufacturer states, “No incompatibility has been demonstrated with the antibiotics gentamicin, kanamycin, or penicillin.”

Manufacturer lists as incompatible with aminophylline, ampicillin, barbiturates, calcium gluconate, magnesium sulfate, phenytoin (Dilantin).

Sources suggest the following compatibilities:

Rate of administration

Should not be administered intravenously undiluted as a bolus. Severe hypotension and cardiac arrest can occur with too-rapid injection.

Actions

A semi-synthetic antibiotic that quickly converts to active clindamycin. Bacteriostatic with activity against gram-positive aerobes and anaerobes, as well as some gram-negative anaerobes. It inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosome. Widely distributed in most body fluids and tissues. There is no clinically effective distribution to cerebrospinal fluid. Half-life is approximately 3 hours. Excreted in urine and feces in small amounts. Crosses placental barrier. Secreted in breast milk.

Indications and uses

Treatment of serious infections caused by susceptible anaerobic bacteria; treatment of infections due to susceptible strains of streptococcal, pneumococcal, and staphylococcal bacteria in penicillin-allergic patients; or treatment of infections that do not respond or are resistant to other less toxic antibiotics, such as erythromycin. Conditions indicated include septicemia, lower respiratory tract infections (including pneumonia), and skin and skin structure, gynecologic, intra-abdominal, and bone and joint infections.

Contraindications

Known hypersensitivity to clindamycin or lincomycin.

Precautions

To reduce the development of drug-resistant bacteria and maintain its effectiveness, clindamycin should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria. ■ Sensitivity studies are indicated to determine susceptibility of the causative organism to clindamycin. ■ Avoid prolonged use; superinfection caused by overgrowth of nonsusceptible organisms may result. ■ Because its use has been associated with severe colitis, it should be reserved for serious infections in which less toxic antimicrobial agents are inappropriate. ■ 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 clindamycin. ■ Use caution with a history of GI, severe renal, or liver disease, and in patients with a history of asthma or significant allergies. ■ Severe skin reactions such as toxic epidermal necrolysis, some with fatal outcome, have been reported. ■ Serious anaphylactoid reactions have been reported. ■ Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy. ■ Not appropriate to treat meningitis.

Drug/lab interactions

May potentiate neuromuscular blocking agents (e.g., atracurium [Tracrium]) and cause profound respiratory depression. ■ Antagonized by erythromycin. ■ May decrease cyclosporine (Sandimmune) levels. Monitor and adjust dose if necessary.

Side effects

Abdominal pain, abnormal liver function tests, agranulocytosis, anaphylaxis, azotemia, cardiac arrest, CDAD, diarrhea, drug reaction with eosinophilia and systemic symptoms (DRESS), eosinophilia (transient), esophagitis, hypersensitivity reactions, hypotension, injection site reactions, jaundice, leukopenia, metallic taste, nausea, neutropenia (transient), oliguria, polyarthritis (rare), proteinuria, pruritus, pseudomembranous colitis, severe skin reactions (e.g., toxic epidermal necrolysis, acute generalized exanthematous pustulosis [AGEP], erythema multiforme), skin rashes, thrombophlebitis, urticaria, vaginitis, vomiting.

Antidote

Notify the physician of any side effects. Discontinue the drug if indicated (e.g., CDAD, diarrhea, hypersensitivity reactions, severe skin reaction), treat hypersensitivity reactions as indicated, and resuscitate as necessary. Mild cases of CDAD may respond to discontinuation of drug. Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. Hemodialysis or CAPD will not decrease blood levels in toxicity.

Pediatric dose

Dose adjustments

Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle provided the patient’s ANC is greater than or equal to 0.75 × 10⁹/L. ■ Reduce dose by 50% in patients with a CrCl between 30 and 60 mL/min. Information is insufficient to make a dose recommendation in patients with a CrCl less than 30 mL/min or in patients on dialysis. ■ Reduce the dose of the next cycle by 25% in patients experiencing a Grade 4 neutropenia (ANC less than 0.5 × 10⁹/L) that lasts 4 or more weeks. ■ Withhold clofarabine if a clinically significant infection develops. When the infection is clinically controlled, restart therapy at full dose. ■ Discontinue if hypotension develops at any time during the 5 days of administration. ■ Discontinue drug immediately if Grade 3 or higher increases in SCr, liver enzymes, or bilirubin occur; see Monitor and Antidote. May be restarted (generally with a 25% dose reduction) when the patient is stable and organ function has returned to baseline. ■ Discontinue drug immediately if S/S of SIRS or capillary leak syndrome occur; see Monitor and Antidote. May be restarted (generally with a 25% dose reduction) when the patient is stable. ■ Withhold clofarabine if a Grade 3 noninfectious nonhematologic toxicity occurs (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea and vomiting that is controlled by antiemetics). With resolution or a return to baseline, restart clofarabine at a 25% dose reduction. ■ Discontinue therapy if a Grade 4 noninfectious nonhematologic toxicity occurs.

Dilution

Compatibility

Manufacturer states, “To prevent drug incompatibilities, no other medications should be administered through the same IV line.”

Rate of administration

A single dose properly diluted and evenly distributed as an infusion over 2 hours.

Actions

A purine nucleoside metabolic inhibitor. Acts by inhibiting DNA synthesis. Also disrupts the mitochondrial membrane, causing the release of mitochondrial proteins, cytochrome C, and apoptosis-inducing factor, which leads to cell death. Is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro. Results in a rapid reduction of peripheral leukemia cells. Metabolism in the liver is very limited. Pathways of nonhepatic elimination not known. Estimated half-life is 5.2 hours. Excreted primarily in the urine.

Indications and uses

Treatment of pediatric patients 1 to 21 years of age with relapsed or refractory acute lymphoblastic leukemia (ALL) after treatment with at least two prior regimens. This indication is based on response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with clofarabine.

Contraindications

Manufacturer states, “None.”

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist in a facility with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ■ At the initiation of treatment, most patients have hematologic impairment as a manifestation of the leukemia. Clofarabine causes myelosuppression, which may be severe and prolonged. Treatment may result in prolonged and severe neutropenia, including febrile neutropenia. Patients may be at an increased risk for infection, including severe and fatal sepsis and opportunistic infections. ■ Use with great caution in patients with impaired hepatic or renal function. ■ May develop tumor lysis syndrome, cytokine release syndrome, systemic inflammatory response syndrome, capillary leak syndrome, and organ dysfunction; deaths have been reported; see Monitor. ■ Serious and fatal hemorrhage, including cerebral, GI, and pulmonary hemorrhage, has occurred. Most cases were associated with thrombocytopenia; see Monitor. ■ Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/M²) used in combination with etoposide (VePesid 100 mg/M²) and cyclophosphamide (Cytoxan 440 mg/M²); has also been reported with monotherapy. ■ Severe and fatal hepatotoxic events, including hepatitis and hepatic failure, have been reported; see Monitor. ■ Renal toxicity, including Grade 3 or 4 elevated creatinine, acute renal failure, and hematuria, have been reported; see Monitor and Dose Adjustments. ■ Fatal and serious cases of enterocolitis (neutropenic colitis, cecitis, and C. difficile colitis) have been reported. Occurs more frequently within 30 days of treatment and in the setting of combination chemotherapy. May lead to necrosis, perforation, hemorrhage, or sepsis complications. ■ Serious and fatal skin reactions (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) have been reported. ■ Safety and effectiveness in adults not established. In a Phase 1 study of adults with refractory and/or relapsed hematologic malignancies, the pediatric dose of 52 mg/M² was not tolerated.

Drug/lab interactions

Clinical drug-drug interactions have not been studied; however, the following cautions should be considered. ■ Primarily excreted by the kidneys; minimize exposure to drugs with known renal toxicity during the 5 days of clofarabine administration (e.g., aminoglycosides [e.g., gentamicin], amphotericin B, NSAIDs [e.g., ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn)], rifampin [Rifadin]). Risk of renal toxicity may be increased. ■ The liver is a known target organ for toxicity; consider avoiding drugs known to induce hepatic toxicity (e.g., amiodarone [Nexterone], NSAIDs [e.g., ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn)], phenothiazines [e.g., prochlorperazine (Compazine)], zidovudine [AZT, Retrovir]). ■ Close monitoring is required with concomitant administration of medications affecting blood pressure or cardiac function (e.g., diuretics [furosemide (Lasix)], calcium channel blockers [diltiazem (Cardizem)], and other antihypertensives). ■ Cytochrome P₄₅₀ inhibitors (e.g., cimetidine [Tagamet], erythromycins, antifungal agents [e.g., itraconazole (Sporanox)], ritonavir [Norvir], verapamil) and cytochrome P₄₅₀ inducers (e.g., carbamazepine [Tegretol], phenobarbital, phenytoin [Dilantin], rifampin [Rifadin]) are unlikely to affect the metabolism of clofarabine. The effect on cytochrome P₄₅₀ substrates has not been studied.

Side effects

Bone marrow suppression (e.g., anemia, leukopenia, neutropenia, thrombocytopenia) is anticipated, appears to be dose dependent, and is usually reversible. Anxiety, diarrhea, fatigue, febrile neutropenia, fever, flushing, headache, mucosal inflammation, nausea and vomiting, palmar-plantar erythrodysesthesia syndrome, pruritus, and rash occur most frequently. SIRS/capillary leak syndrome (e.g., rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multiorgan failure) has occurred and can be fatal. Hepatotoxicity (elevated AST, ALT, bilirubin), renal toxicity (elevated SCr, acute renal failure), and veno-occlusive disease of the liver have occurred. Serious and fatal hemorrhage (cerebral, GI, and pulmonary), enterocolitis (neutropenic colitis, cecitis, and C. difficile colitis), and skin reactions (SJS and TEN) have been reported. Numerous additional side effects may occur and include abdominal pain, anorexia, arthralgia, back pain, cardiac toxicity (e.g., pericardial effusion, tachycardia), confusion, constipation, cough, depression, dermatitis, dizziness, dyspnea, edema, elevated creatinine, epistaxis, erythema, gingival bleeding, hematuria, hepatobiliary toxicity (e.g., elevated AST, ALT, bilirubin), hepatomegaly, hypertension, hypotension, infections (e.g., bacteremia, cellulitis, herpes simplex, oral candidiasis, pneumonia, sepsis, staphylococcal), injection site pain, irritability, jaundice, lethargy, myalgia, pain, petechiae, pleural effusion, renal toxicity, respiratory distress, rigors, somnolence, sore throat, transfusion reaction, tremor, weight loss.

Antidote

Keep physician informed of all side effects; most will be treated symptomatically as indicated. Discontinue if hypotension develops at any time during the 5 days of administration. Discontinue clofarabine immediately if early S/S of SIRS or capillary leak (e.g., hypotension) appear. Use of albumin, diuretics, and steroids may be indicated. May consider restarting (usually at a lower dose) after the patient is stabilized and organ function has returned to baseline. Discontinue clofarabine immediately if substantial increases in SCr, liver enzymes, or bilirubin occur. May be restarted (possibly at a lower dose) when the patient is stable and organ function has returned to baseline. Discontinue clofarabine for exfoliative or bullous rash or if SJS or TEN is suspected. Bone marrow suppression must be resolved before additional doses can be given. Administration of whole blood products (e.g., packed RBCs, platelets, or 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. Use specific antibiotics to combat infection. No specific antidote for overdose. Supportive therapy as indicated will help sustain the patient in toxicity. Should a hypersensitivity reaction occur, treat with antihistamines, corticosteroids, epinephrine, and oxygen as indicated. Resuscitate if indicated.

Usual dose

Pediatric dose

See Usual Dose. Clinical studies were conducted with dosing determined according to body weight and not according to age. See Maternal/Child.

Dose adjustments

Dose and administration interval may be adjusted based on the severity of the bleeding and the degree of hemostasis achieved. If patient develops intravascular coagulation or thrombosis, dosage should be reduced or treatment stopped; see Monitor.

Dilution

NovoSeven RT is room temperature stable (RTS); aseptic technique is imperative. Available in packages that contain 1-, 2-, or 5-mg vials with a specified volume of histidine diluent. Select the appropriate vial package based on the calculated dose. Bring vial and diluent to RT. Do not exceed 37° C (98.6° F). Reconstitute powder with provided diluent, aiming the needle (20- to 26-gauge needle recommended) and the stream of diluent against the side of the vial. Do not inject the diluent directly on the powder. Do not use SWFI or other diluents. Gently swirl vial until powder is completely dissolved. Final concentration of reconstituted solution is 1 mg/mL (1,000 mcg/mL).

Compatibility

Manufacturer states, “Intended for IV injection only and should not be mixed with infusion solutions. Do not store reconstituted solution in syringes.” If line needs to be flushed before or after NovoSeven RT administration, use NS.

Rate of administration

A single dose as a slow IV injection over 2 to 5 minutes, depending on dose administered.

Actions

A vitamin K–dependent glycoprotein structurally similar to human plasma–derived factor VIIa. Produced by recombinant DNA technology. Promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. When complexed with tissue factor, can activate coagulation factor X to factor Xa, and coagulation factor IX to factor IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin. This leads to the formation of a hemostatic plug by converting fibrinogen to fibrin. Half-life is 2.3 hours. Duration of action is 3 hours.

Indications and uses

Treatment of bleeding episodes or prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia. ■ Treatment of bleeding episodes or prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

Contraindications

Manufacturer states, “None.” Use with caution in patients with known hypersensitivity to coagulation factor VIIa (recombinant), any of its components, and in patients with known hypersensitivity to mouse, hamster, or bovine proteins.

Precautions

For intravenous bolus administration only. ■ Should be administered to patients only under the direct supervision of a physician experienced in the treatment of bleeding disorders. ■ Thrombotic events have been reported in clinical trials as well as through post-marketing surveillance following coagulation factor VIIa (recombinant) RTS use for each of the approved indications. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) may have an increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy. Use caution in patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary artery disease (CAD), liver disease, DIC, or postoperative immobilization; elderly patients; and neonates. ■ Coagulation factor VIIa has been studied in placebo-controlled trials outside the approved indications to control bleeding in intracranial hemorrhage, advanced liver disease, trauma, cardiac surgery, spinal surgery, and other therapeutic areas. Safety and effectiveness have not been established in these settings, and the use is not approved by the FDA. Arterial and venous thrombotic and thromboembolic events have been reported during post-marketing surveillance. Studies have shown an increased risk of arterial thromboembolic adverse events (e.g., MI, myocardial ischemia, cerebral infarction, and cerebral ischemia) with coagulation factor VIIa when administered outside the current approved guidelines. ■ Biologic and clinical effects of prolonged elevated levels of factor VIIa have not been studied; therefore, the duration of posthemostatic dosing should be minimized, and patients should be appropriately monitored by a physician experienced in the treatment of hemophilia during this time period.

Drug/lab interactions

The risk of potential interaction between factor VIIa and coagulation factor concentrates has not been adequately evaluated. Simultaneous use of activated prothrombin complex concentrates (e.g., anti-inhibitor coagulant complex [Feiba]) or prothrombin complex concentrates (e.g., factor IX [AlphaNine SD, Benefix]) should be avoided.

Side effects

Generally well tolerated. The majority of patients reporting side effects received more than 12 doses. The most common side effects are arthralgia, edema, fever, headache, hemorrhage, hypertension, hypotension, injection site reaction, nausea, pain, rash, and vomiting. Most serious adverse reactions are thrombotic events; however, the risk in patients with hemophilia and inhibitors is considered to be low. Fatal and nonfatal thrombotic events have been reported when used for both labeled and off-label indications. Other side effects include arthrosis, bradycardia, coagulation disorder, DIC, decreased fibrinogen plasma, decreased prothrombin, decreased therapeutic response, hemarthrosis, hypersensitivity reactions, increased fibrinolysis, pneumonia, pruritus, purpura, renal function abnormalities, shock, subdural hematoma, thrombosis, urticaria.

Antidote

Discontinue drug and notify physician of any major side effects. Treat hypersensitivity reactions as indicated. For thrombosis or DIC, anticoagulation with heparin may be indicated.

Usual dose (international units [IU])

Dose, frequency, and duration must be individualized based on the severity of the factor X deficiency, location and extent of bleeding, patient’s clinical condition, and individual clinical response. Each vial is labeled with the actual factor X potency/content in international units (IU). The dose to achieve a desired in vivo peak increase in factor X level can be calculated with the following formula.

Dose (IU) = Body weight (kg) × Desired factor X rise (IU/dL) × 0.5

The desired factor X rise is the difference between the patient’s plasma factor X level and the desired level. The dosing formula is based on the observed recovery of 2 IU/dL per IU/kg (i.e., for each 1 IU/kg of factor X administered, the circulating factor X level increases by approximately 2 IU/dL).

Dose adjustments

Adjust dose and duration based on factor X levels, location and extent of bleeding, patient’s clinical condition, and clinical response to therapy.

Dilution

Supplied in single-use glass vials containing approximately 250 or 500 IU (approximately 100 IU/mL after reconstitution) of factor X activity, packaged with 2.5 or 5 mL of SWFI, respectively, and a Mix2Vial transfer device. The total number of IUs available is clearly marked on each vial. Record the batch number of each vial. Consult instructions for reconstitution and administration in the package insert. If stored in the refrigerator, warm to room temperature (25° C) before reconstitution. If more than 1 vial is required, use a new Mix2Vial transfer set for each vial of drug. Solution from multiple vials can be pooled into a single syringe. Do not shake. Do not use if the reconstituted solution is cloudy or contains any particles. The reconstituted solution should be clear or a slightly pearl-like solution.

Compatibility

Specific information not available; consider specific use and contact pharmacist.

Rate of administration

A single dose may be administered as an infusion at a rate of 10 mL/min up to a maximum rate of 20 mL/min; consider patient comfort. Reduce rate of administration or interrupt the infusion if a marked increase in pulse occurs.

Actions

Coagulation factor X is a plasma-derived, purified concentrate of human coagulation factor X. It temporarily replaces the missing factor X needed for effective hemostasis. After conversion to its active form (factor Xa), it associates with factor Va to form the prothrombinase complex, which activates prothrombin to thrombin. Thrombin then acts on soluble fibrinogen and factor XIII to generate a cross-linked fibrin clot. Mean half-life is approximately 30.3 hours.

Indications and uses

Treatment of adults and pediatric patients (12 years of age and above) with hereditary factor X deficiency for on-demand treatment and control of bleeding episodes and perioperative management of bleeding in patients with mild hereditary factor X deficiency.

Contraindications

Life-threatening hypersensitivity reactions to coagulation factor X or any of the product components.

Precautions

For IV use only. ​■ ​Administered under the direction of a physician knowledgeable in the treatment of coagulation disorders in a facility with adequate diagnostic and treatment facilities to monitor the patient and respond to any medical emergency. ​■ ​Hypersensitivity reactions, including anaphylaxis, have occurred; see Monitor ​■ ​Manufactured from human plasma. Risk of transmitting infectious agents (e.g., HIV, hepatitis and, theoretically, Creutzfeldt-Jakob disease) has been greatly reduced by screening, testing, and manufacturing techniques. However, risk of transmission cannot be totally eliminated. Health care professionals should use caution during administration; may have risk of exposure to viral infection. ​■ ​Contains trace human proteins other than factor X. ​■ ​Neutralizing antibodies (inhibitors) to factor X may occur; see Monitor.

Drug/lab interactions

Drug interaction studies have not been performed. ​■ ​Use with caution in patients who are receiving other plasma products that may contain factor X (e.g., fresh frozen plasma, prothrombin complex concentrates [e.g., Kcentra]). ​■ ​Based on its mechanism of action, coagulation factor X is likely to be counteracted by direct and indirect factor Xa inhibitors (e.g., apixaban [Eliquis], edoxaban [Savaysa], rivaroxaban [Xarelto]).

Side effects

The most common side effects observed are back pain, fatigue, infusion site erythema, and infusion site pain. Hypersensitivity reactions have occurred.

Antidote

Keep the physician informed of side effects. Slow or interrupt infusion for a marked increase in pulse rate or a mild hypersensitivity reaction. Discontinue the infusion immediately if a severe hypersensitivity reaction occurs. Treat hypersensitivity as necessary (e.g., antihistamines, epinephrine, corticosteroids). Resuscitate as necessary.

Usual dose (international units [IU])

Dose adjustments

Consider increasing dose if adequate trough levels are not achieved.

Dilution

Available as a white lyophilized powder in single-use vials. May contain from 2,000 to 3,125 IU. Actual amount is stated on each vial and each carton. Can be reconstituted using the vial adapter and diluent included with the packaging (see prescribing information) or using a needle and syringe with SWFI as a diluent. Bring vial and diluent to RT (not to exceed 25° C (77° F). Withdraw 3.2 mL of SWFI and inject into the powder by aiming the needle and stream of diluent against the side of the vial. To avoid foaming, do not inject the diluent directly on the powder. Gently swirl to dissolve. Do not shake. A clear and colorless solution. After reconstitution, each mL contains 667 to 1,042 IU.

If a large dose requires the use of multiple vials, reconstitute each additional vial with a separate syringe. For a smaller dose that requires less than the full volume in the vial, the reconstituted solution may be further diluted with NS to facilitate measurement and administration; discard remaining product. Must be used within 3 hours.

Compatibility

Manufacturer states, “Do not administer with other infusion solutions.”

Rate of administration

A single dose as an IV injection at a rate not to exceed 1 to 2 mL/min. Do not administer as a drip infusion.

Actions

A human factor XIII-A₂ homodimer produced by recombinant DNA technology. Factor XIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, factor XIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot. After combining with available factor XIII B-subunits, it has been shown to have the same pharmacodynamics properties in plasma as endogenous factor XIII. Increases the mechanical strength of fibrin clots, retards fibrinolysis, and enhances platelet adhesion to the site of injury. Mean half-life based on baseline (trough) adjusted factor XIII activity was 5.1 days in patients 7 to 58 years of age and 7.1 days in pediatric patients 1 to less than 6 years of age.

Indications and uses

Routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

Contraindications

Known hypersensitivity to the active substance or any of its excipients.

Precautions

For IV injection only. Do not administer as a drip infusion. ■ Should be administered under the supervision of a physician experienced in the treatment of rare bleeding disorders. ■ Hypersensitivity reactions (including anaphylaxis) may occur. ■ Thrombotic events may occur. Use caution in patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary artery disease (CAD), liver disease, DIC, or postoperative immobilization; elderly patients; and neonates. ■ Inhibitory antibodies may occur and should be considered if there is an inadequate response or a reduced therapeutic effect to treatment.

Drug/lab interactions

Concomitant administration with coagulation factor VIIa may cause thrombosis.

Side effects

Headache, increase in fibrin d-dimer levels, injection site pain, and pain in the extremities were most commonly reported and were reported more frequently in pediatric patients 6 to less than 18 years of age. Hypersensitivity reactions (including anaphylaxis) and thromboembolic events are the most serious side effects. Formation of inhibitory antibodies has occurred.

Antidote

Discontinue drug and notify physician of any major side effect. Treat hypersensitivity reactions with oxygen, epinephrine (Adrenalin), antihistamines (e.g., diphenhydramine [Benadryl]), vasopressors (e.g., dopamine), corticosteroids, albuterol, IV fluids, and ventilation equipment as indicated. Resuscitate as necessary.

Usual dose

Dose adjustments

If the serum sodium does not rise at the desired rate, the dose may be titrated up to 40 mg as a continuous infusion over 24 hours. 40 mg is the maximum daily dose. ■ A reduced dose may be required if the patient experiences an undesirably rapid rate of rise of serum sodium; see Precautions. ■ If hyponatremia persists or recurs (after initial interruption of therapy) and the patient has no evidence of neurologic sequelae, conivaptan may be resumed at a reduced dose; see Monitor. ■ A reduced dose may also be required in patients who develop hypotension or hypovolemia; see Monitor. ■ No dose adjustment indicated in patients with mild hepatic impairment. ■ Reduced dose required in patients with moderate hepatic impairment. Initiate with a loading dose of 10 mg. Follow with a continuous infusion of 10 mg over 24 hours for 2 days to a maximum of 4 days. If sodium is not rising at the desired rate, the conivaptan dose may be titrated up to 20 mg/day. ■ Use in patients with severe renal impairment (CrCl less than 30 mL/min) is not recommended; see Contraindications.

Dilution

Available in a single-use, ready-to-use (RTU) plastic container containing 20 mg conivaptan in 100 mL D5W. If the RTU container is being administered as a 40-mg dose, administer two consecutive 20 mg/100 mL containers over 24 hours.

Compatibility

Manufacturer states, “Should not be mixed or administered with lactated Ringer’s or furosemide (Lasix). Should not be combined with any other product in the same intravenous line or bag.”

Rate of administration

Actions

A nonpeptide, dual antagonist of arginine vasopressin (AVP) V_1A and V₂ receptors. The level of AVP in the blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia (in euvolemic hyponatremia there is an increase in total body water, but the sodium content remains the same; in hypervolemic hyponatremia both sodium and water content in the body increase, but the water gain is greater). AVP excess is associated with hyponatremia without edema. The AVP effect is mediated through V₂ receptors that help maintain plasma osmolality. Conivaptan blocks V₂ receptors in the renal collecting ducts, resulting in aquaresis (excretion of free water). This is generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Conivaptan is highly protein bound. It is metabolized in the liver by the cytochrome P₄₅₀ isoenzyme, CYP3A. Its half-life is 5.3 to 8.1 hours, depending on dose. Primarily excreted in the feces and, to a lesser extent, in urine. Crosses the placenta in animals.

Indications and uses

For use in the hospitalized patient to treat euvolemic and hypervolemic hyponatremia. Euvolemic hyponatremia may occur in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH, an inability of the body to excrete dilute urine) or in the setting of certain conditions, including hypothyroidism, adrenal insufficiency, and pulmonary disorders. ■ Not indicated for the treatment of the S/S of heart failure. Raising serum sodium with conivaptan has not been shown to provide a symptomatic benefit.

Contraindications

Patients with hypovolemic hyponatremia. ■ Hypersensitivity to conivaptan or any of its components (propylene glycol, ethanol, lactic acid). ■ Coadministration with potent CYP3A inhibitors, such as clarithromycin, indinavir, itraconazole, ketoconazole, and ritonavir; see Drug Interactions. ■ Premixed solution contains dextrose, which may be contraindicated in patients with a known allergy to corn or corn products. ■ Anuria (no benefit expected).

Precautions

For IV use only. ■ Use only in hospitalized patients. ■ Safety for use in hypovolemic hyponatremic patients with underlying CHF has not been established. Should be used to raise sodium in these patients only after other treatment options have been considered. Incidence of adverse cardiac events may be increased. ■ An overly rapid increase in serum sodium concentration (more than 12 mEq/L/24 hr) may result in serious sequelae. Although not observed in clinical trials, osmotic demyelination syndrome (brain cell dehydration) has been reported following rapid correction of low serum sodium concentration. Osmotic demyelination results in dysarthria, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Patients with severe malnutrition, alcoholism, or advanced liver disease may be at increased risk; use slower rates of correction; see Monitor. ■ Reduced doses required in patients with moderate hepatic impairment; see Dose Adjustments. Impact of severe hepatic impairment has not been studied. ■ May cause significant infusion site reaction; see Monitor.

Drug/lab interactions

A substrate of CYP3A. Coadministration with inhibitors of this enzyme could lead to an increase in conivaptan concentrations, the effect of which is unknown. Concomitant use with potent CYP3A4 inhibitors such as clarithromycin (Biaxin), indinavir (Crixivan), itraconazole (Sporanox), ketoconazole (Nizoral), and ritonavir (Norvir) is contraindicated. ■ A potent inhibitor of CYP3A. May increase plasma concentrations of drugs that are primarily metabolized by this enzyme. Coadministration with amlodipine (Norvasc), midazolam (Versed), and simvastatin (Zocor) resulted in increased concentrations of each of the drugs. Two cases of rhabdomyolysis occurred in patients who were receiving a CYP3A4-metabolized HMG-CoA reductase inhibitor (e.g., simvastatin [Zocor]). Avoid concomitant use with drugs eliminated primarily by CYP3A4-mediated metabolism. Do not initiate subsequent therapy with CYP3A4 substrate drugs until at least 1 week after an infusion of conivaptan. ■ May decrease clearance and increase serum concentration of digoxin. Monitor digoxin levels. ■ Captopril and furosemide (Lasix) do not appear to affect the pharmacokinetics of conivaptan. ■ Does not appear to affect PT/INR when coadministered with warfarin (Coumadin). ■ Does not appear to affect the QT interval.

Side effects

The most common adverse reactions are infusion site reactions (e.g., erythema, pain, phlebitis), fever, headache, hypokalemia, orthostatic hypotension, peripheral edema. Other reactions that occurred in more than 2% of patients include anemia, atrial fibrillation, confusion, constipation, diarrhea, hypertension, hypomagnesemia, hyponatremia, hypotension, insomnia, nausea, pharyngolaryngeal pain, pneumonia, pruritus, pyrexia, ST segment depression on ECG, thirst, urinary tract infection, and vomiting.

Antidote

Notify physician of any side effects. Most will be treated symptomatically. Discontinue therapy if there is an overly rapid increase in serum sodium concentration or if the patient experiences hypotension or hypovolemia. Discontinue therapy permanently if neurologic sequelae are present; see Precautions, Monitor, and Dose Adjustments. Resuscitate as necessary.

Usual dose

25 mg in 1 injection. May be repeated in 6 to 12 hours if indicated.

Dilution

Reconstitute with 5 mL SWFI, directing the flow of diluent gently against the side of the vial. Agitate gently. Do not shake violently. Do not use if discolored or if precipitate is present. Dilution in an IV infusion is not recommended.

Compatibility

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

Manufacturer lists as incompatible with ascorbic acid, protein hydrolysate, or any solution with an acid pH.

According to the manufacturer, infusion with other agents is not generally recommended. May be given at Y-tube if compatible solutions are infusing (NS, dextrose, and invert sugar solutions). According to one source, it is compatible at the Y-site with heparin, hydrocortisone sodium succinate (Solu-Cortef), and potassium chloride (KCl).

Rate of administration

5 mg or fraction thereof over 1 minute. Must be given direct IV or through IV tubing close to needle site. Infusion solution must be compatible. Too-rapid injection may cause flushing.

Actions

A mixture of conjugated estrogens obtained from natural sources. Administration provides a rapid and temporary increase in estrogen levels. Acts at several points on the clotting cascade, enhancing coagulability of the blood, especially in the capillary beds. Promptly corrects bleeding due to estrogen deficiency. Widely distributed in the body. Metabolized primarily in the liver and excreted in the urine. Secreted in breast milk.

Indications and uses

Treatment of abnormal uterine bleeding caused by hormonal imbalance in the absence of organic pathology. Indicated for short-term use only to provide a rapid and temporary increase in estrogen levels.

Contraindications

Known, suspected, or history of breast cancer, active deep venous thrombosis, or pulmonary embolism. ■ A history of or active arterial thromboembolic disease (e.g., stroke, MI). ■ Known or suspected estrogen-dependent neoplasia, pregnancy, undiagnosed abnormal genital bleeding, liver dysfunction or disease. ■ Hypersensitivity to this product or its ingredients (e.g., known anaphylactic reaction and angioedema). ■ Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. ■ Other specific contraindications for estrogens must be considered.

Precautions

IV therapy with conjugated estrogens is indicated for short-term use. However, warnings and precautions associated with oral therapy should be considered (e.g., changes in vaginal bleeding, headache, hypersensitivity reactions, skin reactions, and many more); see Precautions and prescribing information. ■ Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. ■ Even though bleeding is controlled, the etiology of the bleeding must be determined and definitive therapy instituted. ■ May cause fluid retention. Use with caution in patients with cardiac or renal dysfunction. ■ Use with caution in asthma, diabetes, endometriosis, epilepsy, hepatic hemangiomas, hepatic or gallbladder disease, hypercalcemia or hypocalcemia, hypercholesterolemia, hypertension, hypertriglyceridemia, hypoparathyroidism, migraines, obesity, porphyria, systemic lupus erythematosus, or tobacco use; may exacerbate condition. ■ May induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema. ■ Retinal vascular thrombosis has been reported in patients receiving estrogen therapy. Discontinue therapy and obtain ophthalmologic exam if visual disturbances occur. ■ Patients dependent on thyroid hormone replacement therapy (e.g., levothyroxine [Synthroid]) who are also receiving estrogen may require dose adjustment of thyroid replacement medication. ■ Estrogens may increase the risk of deep venous thrombosis, MI, pulmonary embolism, stroke, breast cancer, endometrial cancer, and dementia. ■ Follow immediately with oral estrogens as recommended for dysfunctional uterine bleeding.

Drug/lab interactions

May decrease effects of oral antidiabetics. ■ Barbiturates (e.g., phenobarbital), carbamazepine (Tegretol), phenytoin (Dilantin), rifampin (Rifadin), and St. John’s wort increase metabolism and decrease serum levels and effects. ■ Plasma concentrations may be increased with coadministration of clarithromycin (Biaxin), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), ritonavir (Norvir), and grapefruit juice. ■ May decrease metabolism and increase serum levels of cyclosporine. May increase risk of cyclosporine toxicity. ■ Increased risk of hepatotoxicity with other hepatotoxic agents (e.g., dantrolene [Dantrium]). ■ May increase blood glucose levels and serum lipids. ■ May reduce response to metyrapone test. ■ May alter numerous coagulation tests, glucose tolerance, and thyroid and other protein-binding tests.

Side effects

Rare when used as directed; flushing, nausea, vomiting. IV therapy with conjugated estrogens is indicated for short-term use. However, the numerous adverse reactions associated with oral therapy should be considered (e.g., changes in vaginal bleeding, headache, hypersensitivity reactions, skin reactions, and many more); see Precautions and prescribing information.

Antidote

No toxicity has been reported throughout years of clinical use. Discontinue if jaundice occurs. Discontinue immediately if DVT, MI, PE, stroke, or venous thromboembolism occurs.

Usual dose

250 mcg (0.25 mg). Up to 750 mcg (0.75 mg) has been used.

Pediatric dose

Dilution

Available as a lyophilized powder or as a solution. Reconstitute powder with 1 mL NS. For IV use, both formulations should be diluted with 2 to 5 mL of NS. May be given directly IV after this initial dilution or further diluted in D5W or NS and given as an infusion (250 mcg in 250 mL equals 1 mcg/mL).

Compatibility

Manufacturer states, “Should not be added to blood or plasma; may be inactivated by enzymes.” Consider specific use.

Rate of administration

Actions

A synthetic form of adrenocorticotropic hormone (ACTH). Stimulates the adrenal cortex to secrete adrenocortical hormone. Does not increase cortisol secretion in patients with primary adrenocortical insufficiency. Peak plasma cortisol levels occur in 1 to 2 hours depending on formulation used.

Indications and uses

Diagnostic aid for adrenocortical insufficiency.

Contraindications

Hypersensitivity to cosyntropin.

Precautions

The liquid formulation of cosyntropin is for IV use only. Cortrosyn may be used IV or IM. ■ Preferable to ACTH because it is less likely to cause hypersensitivity reactions; however, hypersensitivity reactions have occurred. Administer in a facility equipped to monitor the patient and respond to any medical emergency. ■ May be used in patients who have had a hypersensitivity reaction to ACTH.

Drug/lab interactions

Plasma cortisol may be falsely elevated with cortisone, hydrocortisone, or spironolactone. Patients receiving cortisone, hydrocortisone, or spironolactone should omit their pretest doses on the day of testing. ■ Abnormally high basal plasma cortisol levels may also occur in patients taking inadvertent doses of cortisone or hydrocortisone on the test day and in women taking drugs that contain estrogen. ■ Many drug reactions are possible with corticosteroids, but usually not a concern with specific diagnostic use. ■ May accentuate electrolyte loss associated with diuretic therapy.

Side effects

Bradycardia, hypertension, peripheral edema, rash, and tachycardia have been reported. Hypersensitivity reactions, including anaphylaxis (rare), have occurred.

Antidote

Notify the physician of any side effect. Keep epinephrine and diphenhydramine available to treat anaphylaxis. Resuscitate as necessary.

Usual dose

Although effective alone in susceptible malignancies, cyclophosphamide is more frequently used concurrently or sequentially with other antineoplastic agents. Doses may be expressed in mg/kg or mg/M². During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis and thus reduce the risk of urinary toxicity. Cyclophosphamide should be administered in the morning; see Monitor.

Pediatric dose

Dose adjustments

Dosages must be adjusted based on antitumor activity and/or leukopenia. Total leukocyte count is a good, objective guide for regulating dosage. Withhold therapy in patients with neutrophils less than or equal to 1,500/mm³ and platelets less than 50,000/mm³. ■ When used as a component of a multidrug regimen, it may be necessary to reduce the dose of cyclophosphamide as well as the doses of the other drugs. ■ Dosing should be cautious in the elderly. Lower-end initial doses may be indicated. Consider decrease in cardiac, hepatic, and renal function; concomitant disease; or other drug therapy; see Elderly.

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

Rate may vary depending on protocol. May be given by IV push or as an intermittent or continuous infusion. Inject or infuse very slowly to reduce the likelihood of adverse reactions that may be administration rate–dependent (e.g., facial swelling, headache, nasal congestion, scalp burning). Duration of infusion should be appropriate for the volume to be infused.

Actions

An alkylating agent of the nitrogen mustard group with antitumor activity; cell cycle phase nonspecific, but most effective in S phase. Cyclophosphamide is a prodrug that is activated by hepatic microsomal enzymes. It is thought to prevent cell division by cross-linking DNA strands and preventing DNA synthesis. Elimination half-life is 3 to 12 hours. Metabolized in the liver, it or its metabolites are excreted in the urine. Secreted in breast milk.

Indications and uses

Although effective alone in susceptible malignancies, cyclophosphamide is more frequently used concurrently or sequentially with other antineoplastic agents. Cyclophosphamide has been used in the treatment of the following malignancies: malignant lymphomas (e.g., Hodgkin’s disease, lymphocytic lymphoma, mixed-cell–type lymphomas, histiocytic lymphoma, Burkitt’s lymphoma), multiple myeloma, leukemias (e.g., chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, acute lymphoblastic [stem cell] leukemia in children), mycosis fungoides, neuroblastoma, adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. ■ Adjuvant treatment of operable node-positive breast cancer in combination with doxorubicin and docetaxel. ■ Used orally to treat many other indications, including biopsy-proven nephrotic syndrome, in pediatric patients when disease fails to respond to primary therapy or when primary therapy causes intolerable side effects.

Contraindications

Hypersensitivity to cyclophosphamide, any of its metabolites, or to other components of the product. ■ Urinary outflow obstruction.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Administered by or under the direction of the physician specialist. ■ Myelosuppression (leukopenia, neutropenia, thrombocytopenia, and anemia), bone marrow failure, and severe immunosuppression may lead to serious and sometimes fatal infections. Sepsis and septic shock can occur. Latent infections (e.g., tuberculosis, viral hepatitis) can be reactivated. ■ Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported. Urotoxicity can be fatal. ■ Exclude or correct any urinary tract obstructions before starting treatment; see Contraindications. ■ Use with caution, if at all, in patients with active urinary tract infections. ■ Myocarditis, myopericarditis, pericardial effusions including cardiac tamponade, and congestive heart failure have been reported and may be fatal. Supraventricular and ventricular arrhythmias (including severe QT prolongation) have been reported. Risk of cardiotoxicity may be increased with high doses, in the elderly, in patients with pre-existing cardiac disease, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic drugs (e.g., bleomycin, doxorubicin). ■ Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, and other forms of pulmonary toxicity leading to respiratory failure have been reported during and after treatment with cyclophosphamide. Late-onset pneumonitis (greater than 6 months after the start of therapy) appears to be associated with increased mortality. Pneumonitis may develop years after treatment. ■ Development of secondary malignancies has been reported in patients treated with cyclophosphamide used alone or in association with other antineoplastic agents. May develop several years after treatment has been discontinued. ■ Risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. ■ Veno-occlusive liver disease (VOD) has been reported. Fatalities have occurred. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term, low-dose, immunosuppressive doses of cyclophosphamide; in patients with pre-existing hepatic impairment; in patients who have received abdominal radiation; and in patients with low performance status. ■ Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome that resembles syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. ■ Use caution in patients with impaired renal function. ■ Use with caution in patients with impaired hepatic function. Reduced conversion to active metabolite may cause decreased efficacy. ■ May interfere with normal wound healing. ■ Do not administer any live virus vaccine to patients receiving antineoplastic drugs. ■ Anaphylaxis resulting in death has been reported.

Drug/lab interactions

Severe myelosuppression may be expected in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy. ■ Concomitant use of protease inhibitors (e.g., atazanavir [Reyataz], indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir], saquinavir [Invirase]) may increase the concentration of cytotoxic metabolites. Use of protease inhibitor–based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than in patients receiving a nonnucleoside reverse transcriptase inhibitor–based regimen (e.g., delavirdine [Rescriptor], nevirapine [Viramune]). ■ Increased hematotoxicity and/or immunosuppression may result from the combined effect of cyclophosphamide and ACE inhibitors (e.g., enalapril [Vasotec], lisinopril [Prinivil, Zestril]), allopurinol (Aloprim), natalizumab (Tysabri), paclitaxel (Taxol), thiazide diuretics (e.g., hydrochlorothiazide), and zidovudine (AZT, Retrovir). ■ Cardiotoxicity may result from a combined effect of cyclophosphamide and anthracyclines (e.g., doxorubicin [Adriamycin], liposomal doxorubicin [Doxil], epirubicin [Ellence]), cytarabine (ARA-C), pentostatin (Nipent), radiation therapy of the cardiac region, and trastuzumab (Herceptin). ■ Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and amiodarone (Nexterone), filgrastim (Neupogen), and sargramostim (Leukine). ■ Increased nephrotoxicity may result from the combined effect of cyclophosphamide and amphotericin B and indomethacin. ■ Risk of hepatotoxicity is increased when administered with azathioprine. ■ Increased incidence of hepatic VOD and mucositis when administered with busulfan (Busulfex, Myleran). ■ Increased incidence of mucositis when administered with protease inhibitors (e.g., atazanavir [Reyataz], indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir], saquinavir [Invirase]). ■ Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment. ■ Higher incidence of noncutaneous malignant solid tumors in patients with Wegener’s granulomatosis when administered with etanercept (Enbrel). ■ Acute encephalopathy has been reported in patients receiving metronidazole (Flagyl) and cyclophosphamide. ■ Concomitant use with tamoxifen (Soltamox) may increase the risk of thromboembolic complications. ■ May increase or decrease activity of anticoagulants (e.g., warfarin [Coumadin]); monitor INR and adjust dose as indicated. ■ May reduce serum digoxin (Lanoxin) and cyclosporine (Sandimmune, Neoral) levels. ■ May prolong neuromuscular blockade and prolonged respiratory depression caused by succinylcholine. These effects are dose dependent and may occur up to several days after cyclophosphamide is discontinued. Alert the anesthesiologist. ■ May decrease effectiveness of oral quinolone antibiotics (e.g., ciprofloxacin [Cipro], levofloxacin [Levaquin]). ■ Capable of many other interactions.

Side effects

The most commonly reported side effects are alopecia (regrowth may be slightly darker), diarrhea, febrile neutropenia, fever, nausea, neutropenia, and vomiting. Other side effects include abdominal pain, amenorrhea, anorexia, gonadal suppression, impaired wound healing, leukopenia (see Precautions), malaise, mucosal ulcerations, darkening of skin and fingernails, susceptibility to infection, including opportunistic infections.

Antidote

No specific antidote available. Minor side effects will be treated symptomatically if necessary. Discontinue the drug in cases of severe hemorrhagic cystitis. Urotoxicity may require interruption of treatment or cystectomy. Mesna has been used to decrease the incidence of cystitis. Interrupt therapy, reduce dose, or discontinue in patients who have or who develop potentially serious infections. 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. Leukocyte and thrombocyte nadirs are usually reached in the first or second week of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Supportive therapy as indicated will help sustain the patient in toxicity. Cyclophosphamide and its metabolites are dialyzable.

Usual dose

5 to 6 mg/kg of body weight as a single dose 4 to 12 hours before transplantation. Repeat once each day until oral dosage form can be tolerated. Individualized adjustment is imperative and may be required on a daily basis. Administered at ¹/₃ of the oral dose in patients temporarily unable to take oral cyclosporine. Administered in conjunction with adrenal corticosteroids; different regimens used; see prescribing information.

Pediatric dose

Same as adult dose; however, higher doses may be required. See Maternal/Child.

Dose adjustments

Reduced dose may be required in impaired renal function and in patients with severe hepatic impairment. ■ Higher doses may be required in pediatric patients. ■ Lower-end doses may be indicated in the elderly. Consider impaired organ function and concomitant disease or other drug therapy. ■ Cyclosporine (Sandimmune) is not bioequivalent to Neoral (a brand of cyclosporine oral solution). Conversion from Neoral dosing to Sandimmune may result in lower cyclosporine blood concentrations. Blood concentration monitoring is indicated to avoid potential underdosing. ■ See Monitor and Drug/Lab Interactions.

Dilution

Each 50 mg should be diluted immediately before use with 20 to 100 mL of NS or D5W and given as an infusion. May leach phthalate from polyvinylchloride containers; use diluents in glass infusion bottles. Dilute immediately before use and discard unused portion.

Compatibility (underline indicates conflicting compatibility information)

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

Leaches out plasticizers, including DEHP from PVC infusion bags and IV tubing; use of non-PVC containers and IV tubing recommended.

One source suggests the following compatibilities:

Rate of administration

A single dose properly diluted as a slow IV infusion equally distributed over 2 to 6 hours.

Actions

A potent immunosuppressive agent. Interferes with IL-2 production and blocks T-cell proliferative signals during early T-cell activation. Prolongs survival of kidney, liver, and heart allogeneic transplants in the human. Measured by specific or nonspecific assays. Extensively metabolized by the cytochrome P₄₅₀ hepatic enzyme system. Half-life is 19 hours (range 10 to 27 hours). Primarily excreted in bile and to a small extent in urine. Crosses the placental barrier. Secreted in breast milk.

Indications and uses

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants in conjunction with adrenocortical steroids. ■ Treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Reserve parenteral formulation for when oral administration not feasible.

Contraindications

Hypersensitivity to cyclosporine or to Cremophor EL (polyoxyethylated castor oil).

Precautions

Anaphylactic reactions have been reported with the IV formulation. These reactions may be related to the IV vehicle Cremophor EL; patients who experienced these reactions have subsequently been treated with the oral formulation of cyclosporine without incident. Because of the risk of anaphylaxis, IV cyclosporine should be reserved for patients who are unable to take oral therapy. ■ Usually administered in the hospital by or under the direction of a physician experienced in immunosuppressive therapy and management of organ transplant patients. ■ Adequate laboratory and supportive medical resources must be available. ■ All formulations may be given concomitantly with adrenocortical steroids. Manufacturer has a Black Box Warning. Do not administer cyclosporine with any other immunosuppressive agent except adrenocortical steroids. ■ Can cause hepatotoxicity and nephrotoxicity; see Monitor. In impaired renal function, if rejection is severe, try other immunosuppressive therapy or allow rejection and removal of the kidney rather than increase dose of cyclosporine. ■ May cause lymphomas and other malignancies, particularly those of the skin. Increased risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression. Some malignancies may be fatal. ■ Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk for infections (viral, bacterial, fungal, protozoal). Both generalized and localized infections can occur. Opportunistic infections include polyomavirus infections (e.g., JC virus–associated progressive multifocal leukoencephalopathy [PML]; polyoma virus–associated nephropathy [PVAN], especially due to BK virus infection). Pre-existing infections may be aggravated. Latent infections may be reactivated. Fatal outcomes have been reported. ■ Encephalopathy has been reported, including posterior reversible encephalopathy syndrome (PRES). May be manifest as impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders, and psychiatric disturbances. Predisposing factors may include hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood levels, and graft-versus-host disease. Patients receiving liver transplants may be more susceptible to encephalopathy than patients receiving kidney transplants. Reversal of encephalopathy has occurred after discontinuation or dose reduction of cyclosporine. ■ Convulsions have been reported, particularly in patients receiving concomitant therapy with high-dose methylprednisolone. ■ Significant hyperkalemia (sometimes associated with hyperchloremic acidosis) and hyperuricemia have been reported. ■ A syndrome of thrombocytopenia and microangiopathic hemolytic anemia that may result in graft failure has been reported. ■ Optic disc edema, including papilledema, with possible visual impairment secondary to benign intracranial hypertension has been reported. ■ See Drug/Lab Interactions.

Drug/lab interactions

Interactions are numerous and potentially life threatening. Review of drug profile by pharmacist imperative. ■ Risk of nephrotoxicity increased when given with other drugs that may potentiate renal dysfunction. Use extreme caution and monitor renal function closely. If impairment of renal function is significant, either reduce the dose of cyclosporine and/or the coadministered drug, or consider an alternative treatment. Manufacturer lists antibiotics (e.g., ciprofloxacin [Cipro], gentamicin, tobramycin, sulfamethoxazole/trimethoprim, vancomycin), antifungals (e.g., amphotericin B, ketoconazole [Nizoral]), anti-inflammatory drugs (e.g., azapropazon [Rheumox], colchicine, diclofenac [Voltaren, Cataflam], naproxen [Aleve, Naprosyn], sulindac [Clinoril]), H₂ antagonists (e.g., cimetidine [Tagamet], ranitidine [Zantac]), immunosuppressives (e.g., tacrolimus [Prograf]), antineoplastics (e.g., melphalan [Alkeran], methotrexate), and fibric acid derivatives (e.g., fenofibrate [Tricor]). Other sources list acyclovir (Zovirax), foscarnet (Foscavir), selected quinolones (e.g., norfloxacin [Noroxin]), and numerous other nephrotoxic drugs. ■ Concurrent administration with colchicine may cause cyclosporine toxicity (e.g., GI, hepatic, renal, and neuromuscular toxicity). Cyclosporine may decrease the clearance and increase the toxic effects of colchicine (e.g., myopathy, neuropathy), especially in patients with renal impairment. With concurrent use, close clinical observation is required. Reduce colchicine dose or discontinue as indicated. ■ May increase diclofenac (Voltaren) serum levels with concomitant administration; initiate diclofenac dose at the lower end of the therapeutic range. ■ Cyclosporine is extensively metabolized by CYP3A4 and is a substrate of the multidrug efflux transporter P-glycoprotein. Drugs that inhibit or induce CYP3A4, P-glycoprotein transporter, or organic anion transporter proteins will result in an alteration of cyclosporine concentrations. Toxicity or allograft rejection may occur. Compounds that decrease cyclosporine absorption, such as orlistat (Alli), should be avoided. ■ Cyclosporine plasma levels may be increased with concurrent use of protease inhibitors (e.g., boceprevir [Victrelis], indinavir [Crixivan], nelfinavir [Viracept], ritonavir [Norvir], saquinavir [Invirase], telaprevir [Incivek]), which are metabolized by cytochrome P₄₅₀ 3A; use caution. ■ Drugs that inhibit the cytochrome P₄₅₀ system may decrease the metabolism of cyclosporine and increase its serum concentrations. Manufacturer lists allopurinol (Aloprim), amiodarone (Nexterone), antibiotics (e.g., azithromycin [Zithromax], clarithromycin, erythromycin, quinupristin/dalfopristin [Synercid]), antifungals (e.g., fluconazole [Diflucan], itraconazole [Sporanox], ketoconazole [Nizoral], voriconazole [VFEND]), bromocriptine (Parlodel), calcium channel blockers (e.g., diltiazem [Cardizem], nicardipine [Cardene], verapamil), danazol (Danocrine), glucocorticoids (e.g., methylprednisolone [Solu-Medrol]), imatinib (Gleevec), metoclopramide (Reglan), nefazodone, and oral contraceptives. Monitor blood levels with concurrent use to avoid cyclosporine toxicity. ■ Drugs that decrease cyclosporine concentrations should be avoided. Manufacturer lists antibiotics (e.g., nafcillin [Nallpen], rifampin [Rifadin]), anticonvulsants (e.g., carbamazepine [Tegretol], oxcarbazepine [Trileptal], phenobarbital [Luminal], phenytoin [Dilantin]), bosentan (Tracleer), octreotide (Sandostatin), orlistat (Alli, Xenical), terbinafine (Lamisil), ticlopidine (Ticlid), St. John’s wort, and sulfinpyrazone (Anturane). Other sources list sulfamethoxazole/trimethoprim; monitor levels and adjust cyclosporine dose as indicated to avoid transplant rejection. ■ Rifabutin (Mycobutin) may increase metabolism of cyclosporine; use care with concomitant use. ■ Cyclosporine inhibits CYP3A4 and the multidrug efflux transporter P-glycoprotein and may increase plasma concentrations of co-medications that are substrates of CYP3A4, P-glycoprotein, or organic anion transporter proteins. Cyclosporine reduces clearance and may increase blood levels of ambrisentan (Letairis), bosentan (Tracleer), dabigatran (Pradaxa), digoxin (Lanoxin), etoposide (VePesid), methotrexate, NSAIDs, prednisolone, repaglinide (Prandin), sirolimus (Rapamune), and other drugs. May decrease the volume distribution of digoxin and cause toxicity rather quickly. With concurrent use, monitor digoxin levels, reduce digoxin dose, or discontinue as indicated. ■ Concomitant use with NSAIDs, particularly in dehydrated patients, may potentiate renal dysfunction. ■ Avoid concurrent use with bosentan. ■ When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose. ■ Cyclosporine may decrease the clearance of HMG-CoA reductase inhibitors (statins) such as atorvastatin (Lipitor), lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor) and, rarely, fluvastatin (Lescol). Cases of myotoxicity (including muscle pain and weakness, myositis, and rhabdomyolysis) have been reported with concomitant use. Dose reduction of statins is indicated. Statins may be temporarily withheld or discontinued in patients with S/S of myopathy or potential for renal injury, including renal failure, secondary to rhabdomyolysis. ■ Coadministration with aliskiren (Tekturna) is not recommended. ■ May decrease mycophenolate (CellCept) levels. Monitor levels closely when cyclosporine is added or removed from a drug regimen containing mycophenolate. ■ Concurrent use of cyclosporine with imipenem-cilastatin (Primaxin) may increase CNS toxicity of both agents. ■ Potentiates nondepolarizing muscle relaxants (e.g., atracurium [Tracrium]); will prolong neuromuscular blockade. ■ Do not use potassium-sparing diuretics (e.g., spironolactone [Aldactone]); may increase risk of hyperkalemia. Use caution when coadministered with other potassium-sparing drugs (e.g., angiotensin-converting inhibitors [e.g., enalapril (Vasotec), lisinopril (Zestril)], angiotensin II receptor antagonists [e.g., losartan (Cozaar), valsartan (Diovan)]), potassium-containing drugs, and/or in patients on a potassium-rich diet. Hyperkalemia can occur. ■ May cause convulsions with high doses of methylprednisolone. ■ May be given in combination with steroids but has additive effects with other immunosuppressive agents; may increase risk of lymphoma. ■ Concurrent administration with sirolimus (Rapamune) increases blood levels of sirolimus. To minimize the effect on blood levels, administer sirolimus 4 hours after cyclosporine dose. ■ Elevations in SCr have been reported with coadministration of sirolimus and cyclosporine. Effect is usually reversible with cyclosporine dose reduction. ■ Serum levels may increase with chloroquine (Aralen). ■ Avoid use in psoriasis patients receiving other immunosuppressive agents or radiation therapy, including PUVA and UVB. Immunosuppression may be excessive. ■ May increase the plasma concentrations of repaglinide (Prandin), which increases the risk for hypoglycemia. Monitor blood glucose levels closely. ■ Concurrent use with nifedipine (Procardia) has caused gingival hyperplasia; avoid use in patients who develop gingival hyperplasia. ■ High doses of cyclosporine (e.g., IV doses of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., daunorubicin, doxorubicin, mitoxantrone) in cancer patients. ■ Monitor serum creatinine when used with NSAIDs in rheumatoid arthritis patients. ■ Vaccinations may be less effective. Avoid use of live virus vaccines in patients receiving cyclosporine. ■ Grapefruit juice may affect certain enzymes of the P₄₅₀ enzyme system and should be avoided.

Side effects

The most common side effects include gum hyperplasia, hirsutism, hypertension, renal dysfunction, and tremor. Other side effects include acne, convulsions, cramps, diarrhea, encephalopathy, glomerular capillary thrombosis, headache, hepatotoxicity, hyperkalemia, hyperuricemia, hypomagnesemia, infection, leukopenia, lymphoma, microangiopathic hemolytic anemia, nausea and vomiting, paresthesia, skin rash, and thrombocytopenia. Hypersensitivity reactions including anaphylaxis have occurred. Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred rarely.

Antidote

Notify physician of all side effects. Most can be treated symptomatically. Drug may be decreased or discontinued or other immunosuppressive agents utilized. Consider reducing total immunosuppression in transplant patients who develop PML or PVAN; may place graft at risk. Discontinue infusion at the first sign of a severe hypersensitivity reaction. Treat hypersensitivity as indicated; may require oxygen, epinephrine (Adrenalin), antihistamines (e.g., diphenhydramine [Benadryl]), vasopressors (e.g., dopamine), corticosteroids, albuterol, IV fluids, and/or ventilation equipment. Nephrotoxicity, hepatotoxicity, encephalopathy (including PRES), or hematopoietic depression may require temporary reduction of dosage or permanent withholding of treatment. Dialysis is not effective in overdose.​

Usual dose

Dose adjustments

Dose (mg/kg) based on average weight in presence of edema or ascites. ■ Dose reduction may be indicated in impaired hepatic or renal function. ■ See Precautions/Monitor. ■ Usually used with other antineoplastic drugs in specific doses to achieve tumor remission. ■ Withhold or modify dose based on degree of bone marrow suppression; see Monitor.

Dilution

Compatibility (underline indicates conflicting compatibility information)

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

One source suggests the following compatibilities:

Rate of administration

Actions

An antimetabolite and pyrimidine antagonist that interferes with the synthesis of DNA. Cell cycle specific for S phase. Through various chemical processes this deprivation acts more quickly on rapidly growing cells and causes their death. Cytotoxic and cytostatic. A potent bone marrow suppressant. Crosses the blood-brain barrier. Serum half-life averages 1 to 3 hours. Metabolized in the liver and excreted in the urine.

Indications and uses

Induction and maintenance of remission in acute nonlymphocytic leukemia in adults and pediatric patients. Also used for treatment of acute lymphocytic leukemia (ALL), the blast phase of chronic myelocytic leukemia, and acute myelocytic leukemia (AML). ■ Is used intrathecally in the treatment of meningeal leukemia. A liposomal formulation (DepoCyt) is available for intrathecal use only, lipofoam molecules contained in this product are much too large for IV use.

Contraindications

Hypersensitivity to cytarabine, pre-existing drug-induced bone marrow suppression.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ 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. ■ Remissions induced by cytarabine are brief unless followed by maintenance therapy. ■ Use caution with impaired liver or renal function. ■ Severe GI, pulmonary, or CNS toxicity has occurred with experimental cytarabine regimens. Toxicities are different (e.g., reversible corneal toxicity, hemorrhagic conjunctivitis, cerebral and cerebellar dysfunction, severe GI ulceration) from those seen with conventional therapy. Deaths have been reported. ■ Benzyl alcohol may cause a fatal “gasping syndrome” in premature infants.

Drug/lab interactions

May inhibit digoxin absorption. ■ Do not administer any live virus vaccines to patients receiving antineoplastic drugs. ■ May cause acute pancreatitis in patients who previously received l-asparaginase. ■ May antagonize action of gentamicin against Klebsiella. ■ May antagonize antifungal actions of flucytosine (Ancobon). ■ Clearance decreased and toxicity increased with nephrotoxic agents (e.g., aminoglycosides [gentamicin]); may cause neurotoxic symptoms (e.g., ataxia, confusion, lethargy). ■ Concurrent use of high doses of cytarabine with cisplatin may increase ototoxicity.

Side effects

Abdominal pain, bone marrow suppression (e.g., anemia, leukopenia, thrombocytopenia), bone pain, cardiomyopathy, chest pain, conjunctivitis, diarrhea, esophagitis, fever, hepatic dysfunction, hypersensitivity reactions, hyperuricemia, malaise, megaloblastosis, mucosal bleeding, myalgia, nausea, oral ulceration, pancreatitis, peripheral motor and sensory neuropathies, rash, stomatitis, thrombophlebitis, vomiting. Higher than usual dose regimens may cause severe coma, GI ulcerations and peritonitis, personality changes, pulmonary toxicity, somnolence, or death.

Antidote

Notify the physician of all side effects. Most will be treated symptomatically. Some toxicity is necessary to produce remission. Discontinue the drug for serious bone marrow suppression. 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. Drug must be restarted as soon as signs of bone marrow recovery occur, or its effectiveness will be lost. Use corticosteroids for cytarabine syndrome (fever, myalgia, bone pain, occasional chest pain, maculopapular rash, conjunctivitis, malaise). Usually occurs in 6 to 12 hours after administration. Continue cytarabine if patient responds to corticosteriods. There is no specific antidote; supportive therapy as indicated will help to sustain the patient in toxicity.​

Usual dose

150 mg/kg is the maximum recommended dose per infusion.

Dilution

Absolute sterile technique required; contains no preservatives. Available in 20- and 50-mL vials (50 mg/mL); multiple vials may be required. Use only if clear and colorless. Enter vial only once and initiate infusion within 6 hours. Must be completely infused within 12 hours of dilution. See Rate of Administration.

Compatibility

Administration through a separate infusion line recommended. If absolutely necessary, may be piggybacked in a pre-existing line containing NS, ¹/₂NS, dextrose 2.5%, 5%, 10%, or 20% in water or saline. Do not dilute CMV-IGIV more than one part to two parts of any of these solutions.

Rate of administration

Use of an in-line filter (pore size 15 microns [0.2 microns acceptable]) and a constant infusion pump (e.g., IVAC) is required. Begin with a rate of 15 mg/kg/hr. May be increased to 30 mg/kg/hr in 30 minutes if no discomfort or adverse effects. May be increased in another 30 minutes to 60 mg/kg/hr if no discomfort or adverse effects. Do not exceed the 60 mg/kg/hr rate or allow the volume infused to exceed 75 mL/hr regardless of mg/kg/hr dose. Slow rate of infusion at onset of patient discomfort or any adverse reactions. Infusion must be complete within 12 hours of dilution. Subsequent doses may be increased at 15-minute intervals using the same mg/kg/hr rates and adhering to the volume maximum of 75 mL/hr.

Actions

A sterile solution of immunoglobulin G (IgG). Derived from pooled adult human plasma selected for high titers of antibody for cytomegalovirus (CMV). Purified by a specific process. Can raise the relevant antibody levels sufficiently to attenuate or reduce the incidence of serious CMV disease. Antibody levels will last 2 to 3 weeks. Recent studies of combined prophylaxis with CMV-IGIV and ganciclovir have shown reductions in the incidence of serious CMV-associated disease in CMV-seronegative recipients of CMV-seropositive organs below that expected from one drug alone.

Indications and uses

Prophylaxis of CMV disease associated with transplantation of kidney, heart, liver, lung, and pancreas. In transplants of these organs other than kidney from CMV-seropositive donors to seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.

Contraindications

History of a prior severe reaction associated with any human immunoglobulin preparations. Individuals with selective immunoglobulin A deficiency may develop antibodies to IgA and are at risk for anaphylaxis.

Precautions

75% of untreated recipients would be expected to develop CMV disease. Use of CMV-IGIV has effected a 50% reduction in this disease rate. Effective results have been obtained with a variety of immunosuppressive regimens (e.g., combinations of azathioprine, cyclosporine, prednisone). ■ A fatal CMV infection occurred even with ganciclovir treatment in one patient, who inadvertently missed a single injection.

Drug/lab interactions

Defer vaccination with any live virus vaccine (e.g., measles, mumps, rubella) until 3 months after CMV-IGIV administration.

Side effects

Incidence related to rate of administration; back pain, chills, fever, flushing, hypotension, muscle cramps, nausea, vomiting, wheezing. Hypersensitivity reactions, including anaphylaxis, are possible.

Antidote

With onset of any minor side effect, reduce rate of infusion immediately or discontinue temporarily. Discontinue CMV-IGIV if symptoms persist, and notify the physician. May be treated symptomatically and infusion resumed at a slower rate if symptoms subside. Discontinue CMV-IGIV if hypotension or anaphylaxis occur and treat immediately. Epinephrine (Adrenalin), diphenhydramine (Benadryl), oxygen, vasopressors (e.g., dopamine), corticosteroids, and ventilation equipment must always be available. Resuscitate as necessary.