Usual dose

Dose adjustments

Dilution

Available as a lyophilized powder in 200-unit vials. Determine the number of vials required using the following calculations:

Weight in kg × Dose/kg desired ÷ 200 (units/vial) = # of vials required

A 60-kg man requiring 60 units/kg would require 3,600 units. The number of vials required would be 18. If necessary, round up to the next whole vial. After patient is weighed and appropriate dose is calculated, remove sufficient vials from refrigerator. Do not leave vials at RT for longer than 24 hours before reconstitution.

Each 200-unit vial must be reconstituted with 5.1 mL of SWFI to yield a reconstituted product with a concentration of 40 units/mL and an extractable volume of 5 mL. Gently swirl to mix the solution. Do not shake. Withdraw exactly 5 mL (40 units/mL) from each 200-unit vial. A total dose must be further diluted with NS to a total volume of 100 to 200 mL. For pediatric patients, a final volume of 100 to 120 mL should be used. For adult patients, a final volume of 130 to 150 mL may be used. However, if the volume of the reconstituted product alone is equal to or greater than 130 to 150 mL, then the final volume should not exceed 200 mL. Mix gently; do not shake. Do not use if discolored or opaque or if particulate matter is present. After dilution, slight flocculation (thin translucent fibers) may occur.

Compatibility

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

Rate of administration

Use of an infusion set with an in-line, low–protein-binding, 0.2-micron filter is required. Use of an infusion pump is helpful. Flush the IV line with NS at the end of the infusion to ensure the total dose is received. Administer as an infusion over 60 to 120 minutes as outlined in the following paragraphs.

Actions

A hydrolytic lysosomal glucocerebroside-specific enzyme. It is produced by recombinant DNA technology using plant cell culture (carrot). An active form of the lysosomal enzyme β-glucocerebrosidase. It catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside normally seen in patients with Gaucher disease. In clinical trials, spleen and liver size were reduced, and anemia and thrombocytopenia were improved. Median terminal half-life was 32.5 minutes in pediatric patients and 28.7 minutes in adult patients. No significant accumulation was noted with repeated dosing.

Indications and uses

Treatment of patients with a confirmed diagnosis of Type 1 Gaucher disease.

Contraindications

Manufacturer states, “None.”

Precautions

Should be used under the direction of a physician knowledgeable in the management of Gaucher disease and administered 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 and Antidote. ■ A therapeutic protein product, patients have developed IgG antidrug antibodies (ADA) to taliglucerase alfa. The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to taliglucerase alfa may be useful in ADA-positive patients or in patients who have experienced hypersensitivity reactions to taliglucerase alfa. Neutralizing antibodies have also been detected in some patients receiving taliglucerase alfa. Clinical relevance as it relates to therapeutic effect is unclear.

Drug/lab interactions

Specific information not available.

Side effects

The most commonly reported adverse reactions in clinical trials were abdominal pain, arthralgia, dizziness, extremity pain, fatigue, flushing, headache, nausea, pruritus, rash, urticaria, and vomiting. Back pain, diarrhea, and hypersensitivity reactions have also been reported.

Antidote

Keep physician informed of side effects; may be treated symptomatically if indicated. Based on the severity of the reaction, temporarily interrupt or discontinue infusion for clinical evidence of a hypersensitivity reaction. Patients have successfully continued therapy after mild hypersensitivity reactions with a reduction in rate of administration and/or treatment or pretreatment with antipyretics, antihistamines (e.g., diphenhydramine [Benadryl]), and/or corticosteroids (e.g., dexamethasone [Decadron]). Discontinue infusion immediately for anaphylaxis and treat 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

200 mg once daily for 6 days as an infusion over 1 hour. Alternately, may be given orally (with or without food).

Dose adjustments

No dose adjustment necessary when changing from IV to oral doses. ​■ ​If a dose is missed or delayed, it should be administered as soon as possible any time up to 8 hours before the next scheduled dose. If less than 8 hours remain before the next dose, wait until the next scheduled dose. ​■ ​No dose adjustments indicated based on age, gender, weight, race, or any degree of hepatic or renal impairment.

Dilution

Available in single-use vials containing 200 mg of tedizolid as a lyophilized powder. Reconstitute the 200-mg vial with 4 mL of SWFI. Gently swirl the contents and let the vial stand until completely dissolved and any foam disperses. Solution should be clear and colorless to pale yellow. Tilt the upright vial and insert a needle attached to a syringe to the bottom corner of the vial. Withdraw 4 mL of the reconstituted solution. Do not invert the vial during extraction of its contents. Further dilute by slowly injecting the 4 mL into a 250-mL bag of NS. Invert the bag gently to mix. Do NOT shake; may cause foaming.

Compatibility

Tedizolid is compatible only with NS. Manufacturer states, “Other IV substances, additives, or other medications should not be added to tedizolid single-use vials or infused simultaneously through the same IV line or through a common IV port. If the same IV line is used for sequential infusion of additional medications, the line should be flushed before and after infusion of tedizolid with NS.” It is incompatible with any solution containing divalent cations (e.g., calcium, magnesium), including LR injection and Hartmann’s solution.

Rate of administration

A single dose as an infusion equally distributed over 1 hour. Do not administer as an IV push or bolus. If a common IV line is used to administer other drugs in addition to tedizolid, flush the IV line before and after each tedizolid infusion with NS.

Actions

Tedizolid phosphate belongs to the oxazolidinone class of antibacterial drugs. It is a phosphate prodrug and is converted to tedizolid by phosphatases. Its antibacterial activity is mediated by binding to the 50S subunit of the bacterial ribosome, resulting in inhibition of protein synthesis. This mechanism of action is different from that of other non–oxazodidinone class antibacterial drugs; therefore cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. Bacteriostatic against designated strains of Staphylococcus, Streptococcus, and Enterococcus; see Indications. Peak plasma concentrations are achieved at the end of the 1-hour infusion. Penetrates into the interstitial space fluid of adipose and skeletal muscle tissue with exposure similar to free-drug exposure in plasma. Approximately 70% to 90% bound to human plasma proteins. Half-life is approximately 12 hours. The majority of elimination occurs via the liver. Primarily excreted as a microbiologically inactive sulfate conjugate in feces with some excretion in urine.

Indications and uses

Treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of designated gram-positive microorganisms, including Staphylococcus aureus (both methicillin-susceptible [MSSA] and methicillin-resistant [MRSA] strains).

Contraindications

Manufacturer states, “None.”

Precautions

For IV use only. ​■ ​Safety and efficacy for use in patients with neutropenia (neutrophil counts less than 1,000 cells/mm³) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. Consider alternative therapy when treating patients with neutropenia and ABSSSI. ​■ ​Specific sensitivity studies are indicated to determine susceptibility of the causative organism to tedizolid. ​■ ​To reduce the development of drug-resistant bacteria and maintain its effectiveness, tedizolid should be used to treat only those infections proven or strongly suspected to be caused by bacteria. ​■ ​Clostridium difficile–associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Consider in patients who present with diarrhea during or after treatment with tedizolid.

Drug/lab interactions

Tedizolid did not detectably inhibit or induce the metabolism of cytochrome P₄₅₀ enzyme substrates. There was no degradation of tedizolid in human liver microsomes, indicating that tedizolid is unlikely to be a substrate for hepatic CYP₄₅₀ enzymes. ​■ ​During in vitro studies, no clinically significant inhibition of any transporter (e.g., the efflux transporter P-glycoprotein ([P-gp], selected OAT, OCT, or ABCG2) was observed. ​■ ​A reversible inhibitor of monoamine oxidase. Not evaluated because subjects taking MAO inhibitors were excluded from trials. ​■ ​In in vitro studies, tedizolid did not demonstrate synergy or antagonism with amphotericin B (conventional), aztreonam (Azactam), ceftazidime (Fortaz), ceftriaxone (Rocephin), ciprofloxacin (Cipro), clindamycin (Cleocin), daptomycin (Cubicin), gentamicin, imipenem-cilastin (Primaxin), ketoconazole (Nizoral), minocycline (Minocin), rifampin (Rifadin), terbinafine (Lamsil), sulfamethoxazole/trimethoprim (Bactrim), or vancomycin.

Side effects

The most common adverse reactions are diarrhea, dizziness, headache, nausea, and vomiting. CDAD, decreased WBC, dermatitis, eye disorders (e.g., asthenopia, blurred vision, visual impairment, vitreous floaters), flushing, hypersensitivity reactions, hypertension, hypoesthesia, increased hepatic transaminases, infusion-related reactions, insomnia, myelosuppression (anemia, neutropenia, thrombocytopenia), oral candidiasis, palpitations, paresthesia, pruritus, seventh nerve paralysis, tachycardia, urticaria, and vulvovaginal mycotic infection have been reported. Peripheral and optic neuropathy have been described in patients treated with another member of the oxazolidinone class (e.g., linezolid [Zyvox]) for longer than 28 days.

Antidote

Notify physician of any side effects. Discontinue the drug if indicated. Treat hypersensitivity reactions as indicated (e.g., diphenhydramine [Benadryl], epinephrine [Adrenalin], albuterol) and resuscitate as necessary. Mild cases of CDAD may respond to discontinuation of tedizolid. Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. In the event of an overdose, discontinue tedizolid and provide supportive treatment as needed. Is not effectively removed from the circulation by hemodialysis.

Usual dose

Dose adjustments

Dose adjustment required in renal impairment as outlined in the following chart.

There is insufficient information to make specific dose recommendations for patients with end-stage renal disease (CrCl less than 10 mL/min), including patients undergoing hemodialysis. ■ Reduced doses may be indicated in the elderly based on age-related renal impairment. ■ No dose adjustment is recommended based on gender or in patients with mild or moderate hepatic impairment. Has not been studied in patients with severe hepatic impairment.

Dilution

Reconstitute each 250-mg vial with 15 mL of D5W, SWFI, or NS (45 mL for a 750-mg vial). Resultant solution has a final concentration of 15 mg/mL. To minimize foaming during reconstitution, allow the vacuum of the vial to pull the diluent from the syringe into the vial. Do not forcefully inject the diluent into the vial. Do not forcefully shake the vial. Reconstitution time is generally under 2 minutes but can occasionally take as long as 20 minutes. Mix thoroughly to dissolve contents completely. Discard vial if vacuum does not pull diluent into vial. Doses of 150 to 800 mg must be further diluted in 100 to 250 mL of D5W, NS, or LR. Doses less than 150 mg or greater than 800 mg must be diluted in a sufficient volume to provide a final concentration of 0.6 to 8 mg/mL. Do not shake the final infusion solution.

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, “Additives or other medications should not be added to telavancin single-use vials or infused simultaneously through the same IV line. If the same IV line is used for sequential infusion of additional medications, the line should be flushed before and after infusions of telavancin with D5W, NS, or LR.”

One source suggests the following compatibilities:

Rate of administration

A single dose equally distributed as an infusion over 60 minutes. Rapid IV infusions can cause “red man syndrome”–like infusion-related reactions, including flushing of the upper body, urticaria, pruritus, or rash. Stopping or slowing the infusion may result in cessation of these reactions.

Actions

A lipoglycopeptide antibacterial that is a synthetic derivative of vancomycin. Bactericidal against gram-positive organisms, including susceptible strains of staphylococci, streptococci, and vancomycin-susceptible enterococci. Exerts bactericidal action through inhibition of cell wall synthesis. Highly protein bound, primarily to albumin. The metabolic pathway for telavancin has not been identified. Half-life is 6.6 to 9.6 hours. Primarily excreted by the kidney.

Indications and uses

Treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of gram-positive microorganisms, including Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, or Enterococcus faecalis (vancomycin-susceptible isolates only). ■ Treatment of adult patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates). Reserve use for when alternative treatments are not suitable.

Contraindications

Known hypersensitivity to telavancin. ■ Use of IV unfractionated heparin sodium is contraindicated; see Drug/Lab Interactions.

Precautions

To reduce the development of drug-resistant bacteria and maintain its effectiveness, telavancin should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria. ■ Sensitivity studies are necessary to determine susceptibility of the causative organism to telavancin. ■ Combination therapy may be clinically indicated if the documented or presumed pathogens include gram-negative organisms. ■ Prolonged use of drug may result in superinfection caused by overgrowth of nonsusceptible organisms. ■ New-onset or worsening renal impairment has been reported. Patients with underlying renal dysfunction or risk factors for renal dysfunction (diabetes mellitus, CHF, or hypertension) may be at increased risk. Patients who received concomitant medications known to affect kidney function (e.g., NSAIDs, ACE inhibitors, and loop diuretics) may also be at higher risk; see Drug Interactions. ■ Patients with pre-existing moderate to severe renal impairment (CrCl less than or equal to 50 mL/min) who were treated with telavancin for HABP/VABP had increased mortality observed versus vancomycin. Use of telavancin in patients with pre-existing moderate to severe renal impairment should be considered only when the anticipated benefit to the patient outweighs the potential risk. ■ Data from cSSSI trials suggest that clinical cure rates were lower in patients with baseline CrCl less than or equal to 50 mL/min. The same decrease in clinical cure rates was not seen in vancomycin-treated patients. These data should be considered when selecting antibacterial therapy for use in patients with baseline moderate/severe renal impairment. ■ Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after the first dose or subsequent doses. Telavancin is a semi-synthetic derivative of vancomycin; it is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin. Use with caution in patients with known hypersensitivity to vancomycin. ■ 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 telavancin. ■ Infusion-related reactions have been reported; see Rate of Administration and Monitor. ■ Has caused prolongation of the QTc interval. Use with caution in patients who are taking drugs known to prolong the QTc interval. Avoid use in patients with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy. ■ Does not interfere with coagulation. Increased risk of bleeding and effects on platelet aggregation have not been observed. However, has been shown to affect certain anticoagulation tests; see Drug/Lab Interactions. ■ There is no known cross-resistance between telavancin and other classes of antibiotics. Some vancomycin-resistant enterococci have a reduced susceptibility to telavancin. ■ See Maternal/Child.

Drug/lab interactions

Use with caution in patients taking medications known to prolong the QTc interval (e.g., amiodarone [Nexterone] and other antiarrhythmics, diphenhydramine [Benadryl], fosphenytoin [Cerebyx], furosemide [Lasix], itraconazole [Sporanox]). Effects may be additive. ■ Concomitant use with other agents that can affect renal function (e.g., NSAIDs [e.g., ibuprofen (Advil, Motrin), naproxen (Naprosyn, Aleve)], diuretics [e.g., furosemide (Lasix)], and ACE inhibitors [e.g., lisinopril (Zestril), enalapril (Vasotec)]) may increase the risk of renal toxicity. ■ Has been administered with aztreonam (Azactam) and piperacillin/tazobactam (Zosyn). There was no effect on the pharmacokinetics of either drug. ■ In vitro studies demonstrate no antagonism between telavancin and amikacin, aztreonam (Azactam), cefepime (Maxipime), ceftriaxone (Rocephin), ciprofloxacin (Cipro), gentamicin, imipenem-cilastatin (Primaxin), meropenem (Merrem), oxacillin (Bactocil), rifampin (Rifadin), and sulfamethoxazole/trimethoprim when tested against telavancin-susceptible staphylococci, streptococci, and enterococci. ■ May affect certain anticoagulation tests. Increases in PT, INR, aPTT, ACT, and coagulation-based factor X activity assays have been observed. Effects dissipate over time. Interference seen when using samples drawn between 0 and 18 hours after telavancin administration. Collect blood samples for these coagulation tests immediately before a patient’s next telavancin dose to minimize interaction. Because aPPT test results are expected to be artificially prolonged after televancin administration, concurrent use of intravenous unfractionated heparin is contraindicated. ■ Interferes with urine qualitative dipstick protein assays and quantitative dye methods (e.g., pyrogallol red-molybdate). However, microalbumin assays are not affected and can be used to monitor urinary protein excretion.

Side effects

The most common side effects include diarrhea, foamy urine, nausea, taste disturbances, and vomiting. Most serious side effects include cardiac events, CDAD, infusion-related reactions, nephrotoxicity (increased SCr, renal insufficiency, renal failure), and respiratory events. The most common events leading to discontinuation of therapy were acute renal failure, nausea, QTc prolongation, and rash. Other reported side effects include abdominal pain, decreased appetite, dizziness, infusion site pain and erythema, pruritus, and rigors.

Antidote

Notify the physician of all side effects. Initiate supportive care as indicated. Infusion-related reactions may respond to temporarily discontinuing or slowing the rate of infusion. Consider alternative antimicrobial therapy in patients who develop renal toxicity. Discontinue telavancin at the first sign of skin rash or other sign of hypersensitivity. Treat CDAD with fluids, electrolytes, protein supplements, and oral vancomycin (Vancocin) or metronidazole (Flagyl) as indicated. In severe cases, surgical evaluation may be indicated. There is no information on the use of hemodialysis or continuous venovenous hemofiltration in toxicity.

Usual dose

IV and oral doses are therapeutically equivalent if the IV dose is administered equally distributed over 90 minutes. The oral form should be used as soon as tolerated by the patient.

Dose adjustments

Newly diagnosed glioblastoma multiforme (GBM):

Temozolomide dose must be adjusted according to the nadir ANC and platelet counts in the previous cycle and the ANC and platelet counts at the time of initiating the next cycle. Obtain a CBC and platelet count weekly during the concomitant phase and as indicated during the 4-week interim before beginning the maintenance phase. Obtain a baseline CBC and platelet count before beginning a cycle and repeat on Day 22 (21 days after the first dose of temozolomide in the cycle or within 48 hours of that day). Repeat weekly until the ANC is above 1.5 × 10⁹/L (1,500/mm³) and the platelet count exceeds 100 × 10⁹/L (100,000/mm³). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. This sequence is repeated for Cycles 1 through 6 of maintenance dosing. Base dose reductions during the next cycle on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during maintenance should be applied according to the following two charts.

Temozolomide Dose Levels for Maintenance Treatment
Dose Level	Dose (mg/M2/day)	Remarks
−1	100 mg/M2/day	Reduction for prior toxicity
0	150 mg/M2/day	Dose during Cycle 1
1	200 mg/M2/day	Dose during Cycles 2 through 6 in absence of toxicity

Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment
Toxicity	Reduce TMZ by 1 Dose Level*	Discontinue TMZ
ANC	<1 × 109/L	See † in footnote
Platelet count	<50 × 109/L	See † in footnote
CTCAE nonhematologic toxicity (except for alopecia, nausea, vomiting)	CTCAE Grade 3	CTCAE Grade 4

*See preceding chart for temozolomide dose levels for maintenance treatment.

^†TMZ is to be discontinued if a dose reduction to <100 mg/M2 is required or if the same Grade 3 nonhematologic toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

TMZ, Temozolomide; CTCAE, Common Terminology Criteria for Adverse Events.

See the next page for temozolomide dose modifications for refractory anaplastic astrocytoma.

Temozolomide Dose Modification Table for Refractory Anaplastic Astrocytoma:

Dilution

Compatibility

No compatibility data available. Manufacturer states, “Other medications should not be infused simultaneously through the same IV line.” May be administered only in the same infusion line as NS.

Rate of administration

A single dose equally distributed over 90 minutes. Use of an infusion pump is recommended. Bioequivalence was established only with the 90-minute infusion. Infusion over a longer or shorter period may result in suboptimal dosing. In addition, the possibility of an increase in infusion-related adverse reactions cannot be ruled out. Flush IV lines before and after temozolomide infusion. Infusion must be complete within 14 hours of reconstitution.

Actions

An imidazotetrazine derivative and alkylating agent. It is not directly active but undergoes rapid nonenzymatic conversion, as dacarbazine does, to the reactive compound 5-(3-methyl triazen-1-yl)-imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite. Cytotoxicity is thought to be due primarily to alkylation of DNA. Weakly bound to plasma proteins. Rapidly eliminated with a mean elimination half-life of 1.8 hours. Some excretion in urine and a very small amount in feces.

Indications and uses

Treatment of adults with newly diagnosed glioblastoma multiforme. Initially given concomitantly with radiotherapy and then continued as maintenance treatment. ■ Treatment of adults with refractory anaplastic astrocytoma (i.e., adults who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine).

Contraindications

Known history of hypersensitivity reaction to temozolomide or any of its components (e.g., urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome). ■ Known history of hypersensitivity to dacarbazine.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Usually 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. ■ Myelosuppression may be severe and dose limiting. May include prolonged pancytopenia, which may result in aplastic anemia. Deaths have been reported. Risk may be increased with concomitant use of other medications associated with aplastic anemia (e.g., carbamazepine [Tegretol], phenytoin [Dilantin], sulfamethoxazole/trimethoprim [Bactrim]). ■ Risk of myelosuppression increased in women and the elderly. ■ Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ■ Prophylaxis against Pneumocystis jiroveci pneumonia (PCP) is required for all patients being treated for newly diagnosed glioblastoma multiforme (a 42-day regimen). The longer dosing regimen may increase the risk of PCP; however, all patients, particularly those receiving steroids, should be monitored for symptoms of PCP regardless of the regimen. ■ Severe, sometimes fatal hepatotoxicity have been reported. ■ Use caution in patients with severe renal or hepatic impairment.

Drug/lab interactions

Valproic acid decreases the oral clearance of temozolomide by about 5%; clinical significance is not known. ■ Administration of live attenuated viral or bacterial vaccines should be avoided.

Side effects

Antidote

Keep physician informed of all side effects and CBC results. Temozolomide may need to be reduced or discontinued. 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. Precautions are indicated for cancer patients with erythropoietin-stimulating agents (ESAs); see darbepoetin alfa and epoetin alfa monographs. Treat hypersensitivity reactions and/or anaphylaxis as indicated (e.g., epinephrine, corticosteroids, oxygen, and antihistamines [diphenhydramine]). There is no specific antidote. Resuscitate as indicated.

Usual dose

Dose adjustments

Hold for absolute neutrophil count (ANC) less than 1,000/mm³, platelet count less than 75,000/mm³, or CTCAE Grade 3 or greater adverse reactions. Once toxicities have resolved to Grade 2 or less, restart therapy with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week. ■ Consider dose reduction to 12.5 mg/week when coadministered with a strong CYP3A4 inhibitor; see Drug Interactions. If the strong inhibitor is discontinued, wait approximately 1 week before adjusting the temsirolimus dose upward to the indicated dose. ■ Consider a dose increase to 50 mg/week when coadministered with a strong CYP3A4 inducer; see Drug Interactions. If the strong inducer is discontinued, the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer. ■ Decrease dose to 15 mg/week in patients with mild hepatic impairment (bilirubin greater than 1 to 1.5 ULN or AST greater than ULN but bilirubin equal to or less than ULN); see Contraindications. ■ No dose adjustment indicated based on age, race, gender, or renal status. Not studied in hemodialysis patients.

Dilution

Compatibility

Manufacturer states, “Final dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.” Non–DEHP-containing materials must be used for administration. Manufacturer also states that undiluted temsirolimus should not be added directly to aqueous infusion solutions. A precipitate will form. In addition, “The stability of temsirolimus in other infusion solutions has not been evaluated. Addition of other drugs or nutritional agents to admixtures of temsirolimus in NS has not been evaluated and should be avoided. Temsirolimus is degraded by both acids and bases, and thus combinations of temsirolimus with agents capable of modifying solution pH should be avoided.”

Rate of administration

A single dose as an infusion equally distributed over 30 to 60 minutes. Use of an infusion pump is recommended. Increase duration of infusion to 60 minutes in patients who experience a hypersensitivity reaction.

Actions

An inhibitor of mTOR (mammalian target of rapamycin). Binds to an intracellular protein (FKBP-12); this protein-drug complex inhibits the activity of mTOR that controls cell division. Results in a cell cycle–specific (G1) growth arrest in treated tumor cells. In in vitro studies, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of hypoxia-inducible factors HIF-1α and HIF-2α and the vascular endothelial growth factor. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements. Extensively metabolized, primarily by cytochrome P₄₅₀ 3A4. Sirolimus is the principal metabolite and is active. Elimination is primarily via the feces and to a small extent via urine. Mean half-lives of temsirolimus and sirolimus were 17.3 and 54.6 hours, respectively.

Indications and uses

Treatment of advanced renal cell carcinoma.

Contraindications

Bilirubin greater than 1.5 ULN; see Dose Adjustments and Precautions.

Precautions

Follow guidelines for handling cytotoxic agents. See Appendix A, p. 1331. ■ Should be administered by or under the direction of the physician specialist in facilities equipped to monitor the patient and respond to any medical emergency. ■ Hypersensitivity/infusion reactions have been reported. May occur early in the first infusion but may also occur with subsequent infusions. Premedication required to minimize the chance of a reaction; see Usual Dose. Use with caution in patients with known hypersensitivity to temsirolimus or its metabolites (including sirolimus) or to any components of the product. Use caution in patients who cannot receive prophylactic treatment with an antihistamine for medical reasons; see Monitor. ■ Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths. Use caution when treating patients with mild hepatic impairment; see Dose Adjustments and Contraindications. ■ Hyperglycemia/glucose intolerance is common. Initiation of or an increase in the dose of insulin and/or oral hypoglycemic agent therapy may be required. ■ Elevated cholesterol and triglycerides are common. Initiation or adjustment of existing therapy may be required. ■ May cause immunosuppression, thus increasing the risk of infections, including opportunistic infections. Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported. May be associated with concomitant use of corticosteroids or other immunosuppressants. ■ Cases of interstitial lung disease, some resulting in death, have been reported. ■ Cases of fatal bowel perforation have been reported. ■ Rapidly progressive and sometimes fatal acute renal failure has occurred. ■ Has been associated with abnormal wound healing. Exercise caution when temsirolimus is used in the perioperative period. ■ Patients who have CNS tumors and/or are receiving anticoagulation therapy may be at increased risk of intracerebral bleeding. ■ The use of live virus vaccines and close contact with those who have received live virus vaccines should be avoided. See Drug Interactions.

Drug/lab interactions

Concomitant use of strong CYP3A4 inhibitors (e.g., amprenavir [Agenerase], atazanavir [Reyataz], clarithromycin [Biaxin], delavirdine [Rescriptor], indinavir [Crixivan], itraconazole [Sporanox], ketoconazole [Nizoral], nefazodone, nelfinavir [Viracept], ritonavir [Norvir], saquinavir [Invirase], telithromycin [Ketek], or voriconazole [VFEND]) may increase plasma concentrations of the active metabolite sirolimus. Avoid concomitant use if possible. If required, consider a dose reduction of temsirolimus to 12.5 mg/week and monitor closely for acute toxicity. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before adjusting the temsirolimus dose upward to the indicated dose; see Dose Adjustments. ■ Grapefruit juice may increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. ■ CYP3A4/5 inducers (e.g., carbamazepine [Tegretol], dexamethasone [Decadron], phenobarbital [Luminal], phenytoin [Dilantin], rifabutin [Mycobutin], rifampin [Rifadin]) may decrease plasma concentrations of the active metabolite sirolimus, thus decreasing effectiveness. Avoid concomitant use if possible. If required, consider a dose increase to 50 mg/week. If the strong inducer is discontinued, the temsirolimus dose should be returned to the dose used before initiating the strong CYP3A4 inducer; see Dose Adjustments. ■ Angioneurotic edema-type reactions (including delayed reactions occurring 2 months after initiation of therapy) have been observed in some patients with concurrent administration of ACE inhibitors (e.g., enalapril [Vasotec]). ■ St. John’s wort may decrease temsirolimus plasma concentrations, decreasing effectiveness. Avoid use. ■ Use caution with other drugs that inhibit the efflux transporter P-glycoprotein (P-gp, ABCB1) (e.g., protease inhibitors [e.g., nelfinavir (Viracept)]); may increase concentrations of temsirolimus. ■ Temsirolimus inhibits P-gp in vitro. Coadministration with drugs that are substrates of P-gp may result in increased concentration of substrates. ■ The combination of sunitinib (Sutent) and temsirolimus resulted in dose-limiting toxicity. ■ Do not administer live virus vaccines to patients receiving temsirolimus, and avoid close contact with those who have received live virus vaccines. ■ No clinically significant effect is anticipated when temsirolimus is coadministered with agents that are metabolized by CYP2D6 or CYP3A4.

Side effects

The most common side effects include anemia, anorexia, asthenia, edema, elevated alkaline phosphatase and AST, elevated SCr, hyperglycemia, hyperlipemia, hypertriglyceridemia, hypophosphatemia, leukopenia, lymphopenia, mucositis, nausea, rash, and thrombocytopenia. Other commonly reported side effects include abdominal pain, acne, arthralgia, chest pain, chills, constipation, convulsions, cough, depression, diarrhea, dry skin, dysgeusia, dyspnea, edema, epistaxis, fever, headache, hemorrhage (GI, rectal), hypokalemia, increased bilirubin, increased total cholesterol, increased triglycerides, infection (pneumonia, URI, wound [including postoperative] sepsis), insomnia, nail disorder, neutropenia, pain, pericardial effusion, pleural effusion, pneumonitis, pruritus, rash, vomiting, and weight loss. The most serious side effects include bowel perforation, hyperglycemia/glucose intolerance, hyperlipemia, hypersensitivity reactions, hypertension, interstitial lung disease, intracerebral hemorrhage, renal failure, venous thromboembolism (including DVT and pulmonary embolus [including fatal outcomes]), and wound healing complications.

Antidote

Keep physician informed of all side effects. Most minor side effects will be treated symptomatically. Monitor patient closely. Discontinue temsirolimus at the first sign of a hypersensitivity reaction. Monitor patient for 30 to 60 minutes. Treatment may be resumed at the discretion of the physician; see Monitor. Treat severe hypersensitivity reactions as indicated; may require epinephrine, airway management, oxygen, IV fluids, antihistamines (e.g., diphenhydramine [Benadryl]), corticosteroids (e.g., hydrocortisone sodium succinate [Solu-Cortef]), and pressor amines (e.g., dopamine). Treat the development of interstitial lung disease as indicated. May require discontinuation of temsirolimus and/or treatment with corticosteroids and/or antibiotics. Some patients have been able to continue therapy without additional intervention.

Usual dose

Initiate therapy as soon as possible after the onset of acute myocardial infarction (AMI) symptoms. Total dose is based on patient weight and should not exceed 50 mg. See the following chart.

Tenecteplase Dosing Guidelines
Patient Weight (kg)	Tenecteplase (mg)	Volume of Tenecteplase* to Be Administered (mL)
<60 kg	30 mg	6 mL
≥60 to <70 kg	35 mg	7 mL
≥70 to <80 kg	40 mg	8 mL
≥80 to <90 kg	45 mg	9 mL
≥90 kg	50 mg	10 mL

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