Altretamine

MEDICATION SAFETY ISSUES
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

International issues:
Hexalen®: Brand name for hexetidine in Greece

U.S. BRAND NAMES — Hexalen®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Miscellaneous

DOSING: ADULTS — Refer to individual protocols.

Ovarian cancer: Oral: 260 mg/m2/day in 4 divided doses for 14 or 21 days of a 28-day cycle
Alternatively (unlabeled use): 4-12 mg/kg/day in 3-4 divided doses for 21-90 days
Alternatively (unlabeled use): 240-320 mg/m2/day in 3-4 divided doses for 21 days, repeated every 6 weeks
Alternatively (unlabeled use): 150 mg/m2/day in 3-4 divided doses for 14 days of a 28-day cycle

DOSING: ELDERLY — Refer to adult dosing.

DOSING: ADJUSTMENT FOR TOXICITY — Temporarily withhold for 14 days or longer, and resume dose at 200 mg/m2/day for any of the following:
Platelet count <75,000/mm3
White blood cell count <2000/mm3 or granulocyte count <1000/mm3
Progressive neurotoxicity
Gastrointestinal intolerance not responsive to antiemetic regimens

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Gelcap:
Hexalen®: 50 mg

DOSAGE FORMS: CONCISE
Gelcap:
Hexalen®: 50 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer total daily dose as 3-4 divided doses after meals and at bedtime.

USE — Palliative treatment of persistent or recurrent ovarian cancer

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Peripheral sensory neuropathy (31%; moderate-to-severe 9%), neurotoxicity (21%; may be progressive and dose limiting)
Gastrointestinal: Nausea/vomiting (33% to 70%; severe 1%), diarrhea (48%)
Hematologic: Anemia (33%), leukopenia (5% to 15%; grade 4: 1%), neutropenia

1% to 10%:
Central nervous system: Fatigue (1%), seizure (1%)
Gastrointestinal: Stomach cramps, anorexia (1%)
Hematologic: Thrombocytopenia (9%)
Hepatic: Alkaline phosphatase increased (9%)

<1% (Limited to important or life-threatening): Alopecia, ataxia, depression, dizziness, hepatotoxicity, mood disorders, pruritus, rash, tremor, vertigo

CONTRAINDICATIONS — Hypersensitivity to altretamine or any component of the formulation; pre-existing severe bone marrow suppression or severe neurologic toxicity; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Bone marrow suppression: . Experienced physician: . Neurotoxicity: .

Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects: Bone marrow suppression: [U.S. Boxed Warning]: Peripheral blood counts should be done routinely before and after drug therapy; bone marrow suppression is common. Use with caution in patients previously treated with other myelosuppressive drugs. Neurotoxicity: [U.S. Boxed Warning]: Neurologic examinations should be done routinely before and after drug therapy; neurotoxicity is common. USe with caution in patients with pre-existing neurotoxicity.

Disease-related concerns: Hepatic impairment: Use with caution in patients with hepatic impairment. Renal impairment: Use with caution in patients with renal impairment.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

DRUG INTERACTIONS
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

MAO Inhibitors: Altretamine may enhance the orthostatic effect of MAO Inhibitors. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Pyridoxine: May diminish the therapeutic effect of Altretamine. Specifically when altretamine is used in combination with Cisplatin the response duration may be diminished. Risk D: Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Tricyclic Antidepressants: Altretamine may enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant while on therapy.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Due to the potential toxicity in the nursing infant, breast-feeding is not recommended.

DIETARY CONSIDERATIONS — Should be taken after meals at bedtime.

PRICING — (data from drugstore.com)
Capsules (Hexalen)
50 mg (100): $1167.31

MONITORING PARAMETERS — CBC with differential, liver function tests; neurologic examination

CANADIAN BRAND NAMES — Hexalen®

INTERNATIONAL BRAND NAMES — Hexalen (AU, BG, GB, IL, JP, NO, NZ, SE, TH); Hexastat (AR, FR, IT, PT); Hexinawas (ES)

MECHANISM OF ACTION — Although altretamine's clinical antitumor spectrum resembles that of alkylating agents, the drug has demonstrated activity in alkylator-resistant patients. The drug selectively inhibits the incorporation of radioactive thymidine and uridine into DNA and RNA, inhibiting DNA and RNA synthesis; reactive intermediates covalently bind to microsomal proteins and DNA; can spontaneously degrade to demethylated melamines and formaldehyde which are also cytotoxic.

PHARMACODYNAMICS / KINETICS
Absorption: Well absorbed (75% to 89%)

Distribution: Highly concentrated hepatically and renally; low in other organs

Protein binding: 50% to 94%

Metabolism: Hepatic; rapid and extensive demethylation to active metabolites (pentamethylmelamine and tetramethylmelamine)

Half-life elimination: 13 hours

Time to peak, plasma: 0.5-3 hours

Excretion: Urine (90%, <1% as unchanged drug)

PATIENT INFORMATION — Report any numbness or tingling in extremities. Nausea and vomiting may occur.

Altretamine

MEDICATION SAFETY ISSUES
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

International issues:
Hexalen®: Brand name for hexetidine in Greece

U.S. BRAND NAMES — Hexalen®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Miscellaneous

DOSING: ADULTS — Refer to individual protocols.

Ovarian cancer: Oral: 260 mg/m2/day in 4 divided doses for 14 or 21 days of a 28-day cycle
Alternatively (unlabeled use): 4-12 mg/kg/day in 3-4 divided doses for 21-90 days
Alternatively (unlabeled use): 240-320 mg/m2/day in 3-4 divided doses for 21 days, repeated every 6 weeks
Alternatively (unlabeled use): 150 mg/m2/day in 3-4 divided doses for 14 days of a 28-day cycle

DOSING: ELDERLY — Refer to adult dosing.

DOSING: ADJUSTMENT FOR TOXICITY — Temporarily withhold for 14 days or longer, and resume dose at 200 mg/m2/day for any of the following:
Platelet count <75,000/mm3
White blood cell count <2000/mm3 or granulocyte count <1000/mm3
Progressive neurotoxicity
Gastrointestinal intolerance not responsive to antiemetic regimens

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Gelcap:
Hexalen®: 50 mg

DOSAGE FORMS: CONCISE
Gelcap:
Hexalen®: 50 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer total daily dose as 3-4 divided doses after meals and at bedtime.

USE — Palliative treatment of persistent or recurrent ovarian cancer

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Peripheral sensory neuropathy (31%; moderate-to-severe 9%), neurotoxicity (21%; may be progressive and dose limiting)
Gastrointestinal: Nausea/vomiting (33% to 70%; severe 1%), diarrhea (48%)
Hematologic: Anemia (33%), leukopenia (5% to 15%; grade 4: 1%), neutropenia

1% to 10%:
Central nervous system: Fatigue (1%), seizure (1%)
Gastrointestinal: Stomach cramps, anorexia (1%)
Hematologic: Thrombocytopenia (9%)
Hepatic: Alkaline phosphatase increased (9%)

<1% (Limited to important or life-threatening): Alopecia, ataxia, depression, dizziness, hepatotoxicity, mood disorders, pruritus, rash, tremor, vertigo

CONTRAINDICATIONS — Hypersensitivity to altretamine or any component of the formulation; pre-existing severe bone marrow suppression or severe neurologic toxicity; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Bone marrow suppression: . Experienced physician: . Neurotoxicity: .

Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects: Bone marrow suppression: [U.S. Boxed Warning]: Peripheral blood counts should be done routinely before and after drug therapy; bone marrow suppression is common. Use with caution in patients previously treated with other myelosuppressive drugs. Neurotoxicity: [U.S. Boxed Warning]: Neurologic examinations should be done routinely before and after drug therapy; neurotoxicity is common. USe with caution in patients with pre-existing neurotoxicity.

Disease-related concerns: Hepatic impairment: Use with caution in patients with hepatic impairment. Renal impairment: Use with caution in patients with renal impairment.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

DRUG INTERACTIONS
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

MAO Inhibitors: Altretamine may enhance the orthostatic effect of MAO Inhibitors. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Pyridoxine: May diminish the therapeutic effect of Altretamine. Specifically when altretamine is used in combination with Cisplatin the response duration may be diminished. Risk D: Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Tricyclic Antidepressants: Altretamine may enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid becoming pregnant while on therapy.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Due to the potential toxicity in the nursing infant, breast-feeding is not recommended.

DIETARY CONSIDERATIONS — Should be taken after meals at bedtime.

PRICING — (data from drugstore.com)
Capsules (Hexalen)
50 mg (100): $1167.31

MONITORING PARAMETERS — CBC with differential, liver function tests; neurologic examination

CANADIAN BRAND NAMES — Hexalen®

INTERNATIONAL BRAND NAMES — Hexalen (AU, BG, GB, IL, JP, NO, NZ, SE, TH); Hexastat (AR, FR, IT, PT); Hexinawas (ES)

MECHANISM OF ACTION — Although altretamine's clinical antitumor spectrum resembles that of alkylating agents, the drug has demonstrated activity in alkylator-resistant patients. The drug selectively inhibits the incorporation of radioactive thymidine and uridine into DNA and RNA, inhibiting DNA and RNA synthesis; reactive intermediates covalently bind to microsomal proteins and DNA; can spontaneously degrade to demethylated melamines and formaldehyde which are also cytotoxic.

PHARMACODYNAMICS / KINETICS
Absorption: Well absorbed (75% to 89%)

Distribution: Highly concentrated hepatically and renally; low in other organs

Protein binding: 50% to 94%

Metabolism: Hepatic; rapid and extensive demethylation to active metabolites (pentamethylmelamine and tetramethylmelamine)

Half-life elimination: 13 hours

Time to peak, plasma: 0.5-3 hours

Excretion: Urine (90%, <1% as unchanged drug)

PATIENT INFORMATION — Report any numbness or tingling in extremities. Nausea and vomiting may occur.

Alteplase

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Activase® may be confused with Cathflo® Activase®, TNKase®
Alteplase may be confused with Altace®
"tPA" abbreviation should not be used when writing orders for this medication; has been misread as TNKase (tenecteplase)

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V.) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

U.S. BRAND NAMES — Activase®; Cathflo® Activase®

PHARMACOLOGIC CATEGORY
Thrombolytic Agent

DOSING: ADULTS
ST-elevation myocardial infarction (STEMI): I.V. (Activase®): Front loading dose (weight-based):
Patients >67 kg: Total dose: 100 mg over 1.5 hours; infuse 15 mg over 1-2 minutes. Infuse 50 mg over 30 minutes. Infuse remaining 35 mg of alteplase over the next hour. See "Note."
Patients ≤ 67 kg: Infuse 15 mg I.V. bolus over 1-2 minutes, then infuse 0.75 mg/kg (not to exceed 50 mg) over next 30 minutes, followed by 0.5 mg/kg over next 60 minutes (not to exceed 35 mg). See "Note."
Note: All patients should receive 162-325 mg of chewable nonenteric coated aspirin as soon as possible and then daily. Administer concurrently with heparin 60 units/kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg/hour (maximum: 1000 units/hour) and adjust to aPTT target of 50-70 seconds (or 1.5-2 times the upper limit of control).

Acute pulmonary embolism: I.V. (Activase®): 100 mg over 2 hours.

Acute ischemic stroke: I.V. (Activase®): Within 3 hours of the onset of symptom onset (labeled use) or within 3-4.5 hours of symptom onset (unlabeled use; del Zoppo, 2009; Hacke, 2008): Note: Initiation of anticoagulants (eg, heparin) or antiplatelet agents (eg, aspirin) within 24 hours after starting alteplase is not recommended; however, initiation of aspirin between 24-48 hours after stroke onset is recommended (Adams, 2007). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial did not increase incidence of intracerebral hemorrhage (Hacke, 2008).
Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)
Patients ≤ 100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an I.V. bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.
Patients >100 kg: Load with 9 mg (10% of 90 mg) as an I.V. bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

Central venous catheter clearance: Intracatheter (Cathflo® Activase® 1 mg/mL):
Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded
Patients ≥ 30 kg: 2 mg (2 mL); retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded

Acute peripheral arterial occlusive disease (unlabeled use): Intra-arterial: 0.02-0.1 mg/kg/hour for up to 36 hours
Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommendation: ≤ 2 mg/hour and subtherapeutic heparin (aPTT <1.5 times baseline)

DOSING: PEDIATRIC — Central venous catheter clearance: Intracatheter: Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded

(For additional information see "Alteplase: Pediatric drug information")

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution, recombinant:
Activase®: 50 mg [29 million int. units; contains polysorbate 80; packaged with diluent]; 100 mg [58 million int. units; contains polysorbate 80; packaged with diluent and transfer device]
Cathflo® Activase®: 2 mg [contains polysorbate 80]

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution, recombinant:
Activase®: 50 mg [29 million int. units]; 100 mg [58 million int. units]
Cathflo® Activase®: 2 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION
Activase®: ST-elevation MI: Accelerated infusion: Bolus dose may be prepared by one of three methods:
1) Removal of 15 mL reconstituted (1 mg/mL) solution from vial
2) Removal of 15 mL from a port on the infusion line after priming
3) Programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion

Activase®: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:
1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)
2) Removal of the appropriate volume from a port on the infusion line after priming
3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion

Note: Remaining dose for STEMI, AIS, or total dose for acute pulmonary embolism may be administered as follows: Any quantity of drug not to be administered to the patient must be removed from vial(s) prior to administration of remaining dose.
50 mg vial: Either PVC bag or glass vial and infusion set
100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial
If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL.

Cathflo® Activase®: Intracatheter: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4-5 mL of blood in patients ≥ 10 kg or 3 mL in patients <10 kg to remove Cathflo® Activase® and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo® Activase® dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.

COMPATIBILITY — Stable in NS, sterile water for injection; incompatible with bacteriostatic water; variable stability (consult detailed reference) in D5W.

Y-site administration: Compatible: Lidocaine, metoprolol, propranolol. Incompatible: Dobutamine, dopamine, heparin, nitroglycerin.

Compatibility when admixed: Compatible: Lidocaine, morphine, nitroglycerin. Incompatible: Dobutamine, dopamine, heparin.

USE — Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries; management of acute ischemic stroke (AIS); management of acute pulmonary embolism

Recommended criteria for treatment:
STEMI: Chest pain ≥ 20 minutes duration, onset of chest pain within 12 hours of treatment (or within prior 12-24 hours in patients with continuing ischemic symptoms), and ST-segment elevation >0.1 mV in at least two contiguous precordial leads or two adjacent limb leads on ECG or new or presumably new left bundle branch block (LBBB)
AIS: Onset of stroke symptoms within 3 hours of treatment
Acute pulmonary embolism: Age ≤ 75 years: Documented massive pulmonary embolism by pulmonary angiography or echocardiography or high probability lung scan with clinical shock

Cathflo® Activase®: Restoration of central venous catheter function

USE - UNLABELED / INVESTIGATIONAL — Acute ischemic stroke presenting 3-4.5 hours after symptom onset; acute peripheral arterial occlusive disease

ADVERSE REACTIONS SIGNIFICANT — As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmia. Note: Lowest rate of bleeding complications expected with dose used to restore catheter function.

1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Fever
Dermatologic: Bruising (1%)
Gastrointestinal: GI hemorrhage (5%), nausea, vomiting
Genitourinary: GU hemorrhage (4%)
Hematologic: Bleeding (0.5% major, 7% minor: GUSTO trial)
Local: Bleeding at catheter puncture site (15.3%, accelerated administration)

<1% (Limited to important or life-threatening): Allergic reactions: Anaphylaxis, anaphylactoid reactions, laryngeal edema, rash, and urticaria (<0.02%); epistaxis; gingival hemorrhage; intracranial hemorrhage (0.4% to 0.87% when dose is ≤ 100 mg); pericardial hemorrhage; retroperitoneal hemorrhage

Additional cardiovascular events associated with use in STEMI: AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia/infarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema, asystole, ventricular tachycardia, bradycardia, ruptured intracranial AV malformation, seizure, hemorrhagic bursitis, cholesterol crystal embolization

Additional events associated with use in pulmonary embolism: Pulmonary re-embolization, pulmonary edema, pleural effusion, thromboembolism

Additional events associated with use in stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke

CONTRAINDICATIONS — Hypersensitivity to alteplase or any component of the formulation

Treatment of STEMI or PE: Active internal bleeding; history of CVA; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; known bleeding diathesis; severe uncontrolled hypertension; suspected aortic dissection

Treatment of acute ischemic stroke: Evidence of intracranial hemorrhage or suspicion of subarachnoid hemorrhage on pretreatment evaluation; intracranial or intraspinal surgery within 3 months; stroke or serious head injury within 3 months; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm; arteriovenous malformation or aneurysm; multilobar cerebral infarction (hypodensity >1/3 cerebral hemisphere; Adams, 2007); clinical presentation suggesting post-MI pericarditis; known bleeding diathesis including but not limited to current use of oral anticoagulants producing an INR >1.7, an INR >1.7, administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT at presentation, platelet count <100,000/mm3.
Additional exclusion criteria within clinical trials:
Presentation <3>400 mg/dL, and arterial puncture at a noncompressible site or lumbar puncture within 1 week.
Presentation 3-4.5 hours after initial symptoms (ECASS-III; Hacke, 2008): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of anticoagulants regardless of INR, glucose level <50>400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25, and history of both stroke and diabetes.

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias. Bleeding: Do not use doses >150 mg; associated with increased risk of intracranial hemorrhage. The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and heparin should be stopped.

Disease-related concerns: Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy: Recent (within 10 days) major surgery (eg, CABG, obstetrical delivery, organ biopsy, pregnancy, previous puncture of noncompressible vessels), prolonged CPR with evidence of thoracic trauma, lumbar puncture within 1 week, cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension (systolic BP >175 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site and/or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location. ST-elevation myocardial infarction (STEMI): Appropriate use: Follow standard management for STEMI while infusing alteplase. Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3-4.5 hours after symptom onset) has now been formally evaluated and shown to be safe and efficacious for select individuals (del Zoppo, 2009; Hacke, 2008).Treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.

Concurrent drug therapy issues: Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. In the treatment of acute ischemic stroke, the current use of oral anticoagulants producing an INR >1.7 is a contraindication. Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation. Heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of acute ischemic stroke, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS, 1995). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke, 2008).

Special populations: Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. Acute ischemic stroke (within 3-4.5 hours after symptom onset): Patients >80 years were excluded from the clinical trial (Hacke, 2008). Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Dosage form specific issues: Cathflo® Activase®: When used to restore catheter function, use Cathflo® cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.

Other warnings/precautions: Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.

DRUG INTERACTIONS
Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk D: Consider therapy modification

Drotrecogin Alfa: Thrombolytic Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk D: Consider therapy modification

Nitroglycerin: May decrease the serum concentration of Alteplase. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. The risk of bleeding may be increased in pregnant women. Use during pregnancy is limited; administer to pregnant women only if the potential benefits justify the risk to the fetus.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS
Acute ischemic stroke: In addition to monitoring for bleeding complications, the 2007 AHA/ASA Guidelines for the early management of acute ischemic stroke recommends the following:
Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.
If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.
Measure BP every 15 minutes for the first 2 hours then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ≥ 180 mm Hg or if a diastolic BP is ≥ 105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.
Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.

Central venous catheter clearance: Assess catheter function by attempting to aspirate blood.

ST-elevation MI: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, prothrombin times, and partial thromboplastin times.

REFERENCE RANGE
Not routinely measured; literature supports therapeutic levels of 0.52-1.8 mcg/mL

Fibrinogen: 200-400 mg/dL

Activated partial thromboplastin time (aPTT): 22.5-38.7 seconds

Prothrombin time (PT): 10.9-12.2 seconds

CANADIAN BRAND NAMES — Activase® rt-PA; Cathflo® Activase®

INTERNATIONAL BRAND NAMES — Actilyse (AE, AR, AT, AU, BD, BE, BF, BG, BH, BJ, BR, CH, CI, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, HK, HN, HU, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, OM, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SY, TH, TN, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Activacin (JP)

MECHANISM OF ACTION — Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

PHARMACODYNAMICS / KINETICS
Duration: >50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes

Excretion: Clearance: Rapidly from circulating plasma (550-650 mL/minute), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes

Alteplase

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Activase® may be confused with Cathflo® Activase®, TNKase®
Alteplase may be confused with Altace®
"tPA" abbreviation should not be used when writing orders for this medication; has been misread as TNKase (tenecteplase)

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V.) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

U.S. BRAND NAMES — Activase®; Cathflo® Activase®

PHARMACOLOGIC CATEGORY
Thrombolytic Agent

DOSING: ADULTS
ST-elevation myocardial infarction (STEMI): I.V. (Activase®): Front loading dose (weight-based):
Patients >67 kg: Total dose: 100 mg over 1.5 hours; infuse 15 mg over 1-2 minutes. Infuse 50 mg over 30 minutes. Infuse remaining 35 mg of alteplase over the next hour. See "Note."
Patients ≤ 67 kg: Infuse 15 mg I.V. bolus over 1-2 minutes, then infuse 0.75 mg/kg (not to exceed 50 mg) over next 30 minutes, followed by 0.5 mg/kg over next 60 minutes (not to exceed 35 mg). See "Note."
Note: All patients should receive 162-325 mg of chewable nonenteric coated aspirin as soon as possible and then daily. Administer concurrently with heparin 60 units/kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg/hour (maximum: 1000 units/hour) and adjust to aPTT target of 50-70 seconds (or 1.5-2 times the upper limit of control).

Acute pulmonary embolism: I.V. (Activase®): 100 mg over 2 hours.

Acute ischemic stroke: I.V. (Activase®): Within 3 hours of the onset of symptom onset (labeled use) or within 3-4.5 hours of symptom onset (unlabeled use; del Zoppo, 2009; Hacke, 2008): Note: Initiation of anticoagulants (eg, heparin) or antiplatelet agents (eg, aspirin) within 24 hours after starting alteplase is not recommended; however, initiation of aspirin between 24-48 hours after stroke onset is recommended (Adams, 2007). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial did not increase incidence of intracerebral hemorrhage (Hacke, 2008).
Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)
Patients ≤ 100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an I.V. bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.
Patients >100 kg: Load with 9 mg (10% of 90 mg) as an I.V. bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

Central venous catheter clearance: Intracatheter (Cathflo® Activase® 1 mg/mL):
Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded
Patients ≥ 30 kg: 2 mg (2 mL); retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded

Acute peripheral arterial occlusive disease (unlabeled use): Intra-arterial: 0.02-0.1 mg/kg/hour for up to 36 hours
Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommendation: ≤ 2 mg/hour and subtherapeutic heparin (aPTT <1.5 times baseline)

DOSING: PEDIATRIC — Central venous catheter clearance: Intracatheter: Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded

(For additional information see "Alteplase: Pediatric drug information")

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution, recombinant:
Activase®: 50 mg [29 million int. units; contains polysorbate 80; packaged with diluent]; 100 mg [58 million int. units; contains polysorbate 80; packaged with diluent and transfer device]
Cathflo® Activase®: 2 mg [contains polysorbate 80]

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution, recombinant:
Activase®: 50 mg [29 million int. units]; 100 mg [58 million int. units]
Cathflo® Activase®: 2 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION
Activase®: ST-elevation MI: Accelerated infusion: Bolus dose may be prepared by one of three methods:
1) Removal of 15 mL reconstituted (1 mg/mL) solution from vial
2) Removal of 15 mL from a port on the infusion line after priming
3) Programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion

Activase®: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:
1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)
2) Removal of the appropriate volume from a port on the infusion line after priming
3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion

Note: Remaining dose for STEMI, AIS, or total dose for acute pulmonary embolism may be administered as follows: Any quantity of drug not to be administered to the patient must be removed from vial(s) prior to administration of remaining dose.
50 mg vial: Either PVC bag or glass vial and infusion set
100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial
If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL.

Cathflo® Activase®: Intracatheter: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4-5 mL of blood in patients ≥ 10 kg or 3 mL in patients <10 kg to remove Cathflo® Activase® and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo® Activase® dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.

COMPATIBILITY — Stable in NS, sterile water for injection; incompatible with bacteriostatic water; variable stability (consult detailed reference) in D5W.

Y-site administration: Compatible: Lidocaine, metoprolol, propranolol. Incompatible: Dobutamine, dopamine, heparin, nitroglycerin.

Compatibility when admixed: Compatible: Lidocaine, morphine, nitroglycerin. Incompatible: Dobutamine, dopamine, heparin.

USE — Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries; management of acute ischemic stroke (AIS); management of acute pulmonary embolism

Recommended criteria for treatment:
STEMI: Chest pain ≥ 20 minutes duration, onset of chest pain within 12 hours of treatment (or within prior 12-24 hours in patients with continuing ischemic symptoms), and ST-segment elevation >0.1 mV in at least two contiguous precordial leads or two adjacent limb leads on ECG or new or presumably new left bundle branch block (LBBB)
AIS: Onset of stroke symptoms within 3 hours of treatment
Acute pulmonary embolism: Age ≤ 75 years: Documented massive pulmonary embolism by pulmonary angiography or echocardiography or high probability lung scan with clinical shock

Cathflo® Activase®: Restoration of central venous catheter function

USE - UNLABELED / INVESTIGATIONAL — Acute ischemic stroke presenting 3-4.5 hours after symptom onset; acute peripheral arterial occlusive disease

ADVERSE REACTIONS SIGNIFICANT — As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmia. Note: Lowest rate of bleeding complications expected with dose used to restore catheter function.

1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Fever
Dermatologic: Bruising (1%)
Gastrointestinal: GI hemorrhage (5%), nausea, vomiting
Genitourinary: GU hemorrhage (4%)
Hematologic: Bleeding (0.5% major, 7% minor: GUSTO trial)
Local: Bleeding at catheter puncture site (15.3%, accelerated administration)

<1% (Limited to important or life-threatening): Allergic reactions: Anaphylaxis, anaphylactoid reactions, laryngeal edema, rash, and urticaria (<0.02%); epistaxis; gingival hemorrhage; intracranial hemorrhage (0.4% to 0.87% when dose is ≤ 100 mg); pericardial hemorrhage; retroperitoneal hemorrhage

Additional cardiovascular events associated with use in STEMI: AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia/infarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema, asystole, ventricular tachycardia, bradycardia, ruptured intracranial AV malformation, seizure, hemorrhagic bursitis, cholesterol crystal embolization

Additional events associated with use in pulmonary embolism: Pulmonary re-embolization, pulmonary edema, pleural effusion, thromboembolism

Additional events associated with use in stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke

CONTRAINDICATIONS — Hypersensitivity to alteplase or any component of the formulation

Treatment of STEMI or PE: Active internal bleeding; history of CVA; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; known bleeding diathesis; severe uncontrolled hypertension; suspected aortic dissection

Treatment of acute ischemic stroke: Evidence of intracranial hemorrhage or suspicion of subarachnoid hemorrhage on pretreatment evaluation; intracranial or intraspinal surgery within 3 months; stroke or serious head injury within 3 months; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm; arteriovenous malformation or aneurysm; multilobar cerebral infarction (hypodensity >1/3 cerebral hemisphere; Adams, 2007); clinical presentation suggesting post-MI pericarditis; known bleeding diathesis including but not limited to current use of oral anticoagulants producing an INR >1.7, an INR >1.7, administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT at presentation, platelet count <100,000/mm3.
Additional exclusion criteria within clinical trials:
Presentation <3>400 mg/dL, and arterial puncture at a noncompressible site or lumbar puncture within 1 week.
Presentation 3-4.5 hours after initial symptoms (ECASS-III; Hacke, 2008): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of anticoagulants regardless of INR, glucose level <50>400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25, and history of both stroke and diabetes.

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias. Bleeding: Do not use doses >150 mg; associated with increased risk of intracranial hemorrhage. The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and heparin should be stopped.

Disease-related concerns: Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy: Recent (within 10 days) major surgery (eg, CABG, obstetrical delivery, organ biopsy, pregnancy, previous puncture of noncompressible vessels), prolonged CPR with evidence of thoracic trauma, lumbar puncture within 1 week, cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension (systolic BP >175 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site and/or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location. ST-elevation myocardial infarction (STEMI): Appropriate use: Follow standard management for STEMI while infusing alteplase. Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3-4.5 hours after symptom onset) has now been formally evaluated and shown to be safe and efficacious for select individuals (del Zoppo, 2009; Hacke, 2008).Treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.

Concurrent drug therapy issues: Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. In the treatment of acute ischemic stroke, the current use of oral anticoagulants producing an INR >1.7 is a contraindication. Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation. Heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of acute ischemic stroke, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS, 1995). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke, 2008).

Special populations: Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. Acute ischemic stroke (within 3-4.5 hours after symptom onset): Patients >80 years were excluded from the clinical trial (Hacke, 2008). Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Dosage form specific issues: Cathflo® Activase®: When used to restore catheter function, use Cathflo® cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.

Other warnings/precautions: Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.

DRUG INTERACTIONS
Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk D: Consider therapy modification

Drotrecogin Alfa: Thrombolytic Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk D: Consider therapy modification

Nitroglycerin: May decrease the serum concentration of Alteplase. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. The risk of bleeding may be increased in pregnant women. Use during pregnancy is limited; administer to pregnant women only if the potential benefits justify the risk to the fetus.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS
Acute ischemic stroke: In addition to monitoring for bleeding complications, the 2007 AHA/ASA Guidelines for the early management of acute ischemic stroke recommends the following:
Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.
If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.
Measure BP every 15 minutes for the first 2 hours then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ≥ 180 mm Hg or if a diastolic BP is ≥ 105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.
Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.

Central venous catheter clearance: Assess catheter function by attempting to aspirate blood.

ST-elevation MI: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, prothrombin times, and partial thromboplastin times.

REFERENCE RANGE
Not routinely measured; literature supports therapeutic levels of 0.52-1.8 mcg/mL

Fibrinogen: 200-400 mg/dL

Activated partial thromboplastin time (aPTT): 22.5-38.7 seconds

Prothrombin time (PT): 10.9-12.2 seconds

CANADIAN BRAND NAMES — Activase® rt-PA; Cathflo® Activase®

INTERNATIONAL BRAND NAMES — Actilyse (AE, AR, AT, AU, BD, BE, BF, BG, BH, BJ, BR, CH, CI, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, HK, HN, HU, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, OM, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SY, TH, TN, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Activacin (JP)

MECHANISM OF ACTION — Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

PHARMACODYNAMICS / KINETICS
Duration: >50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes

Excretion: Clearance: Rapidly from circulating plasma (550-650 mL/minute), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes

Alprostadil

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alprostadil may be confused with alPRAZolam

U.S. BRAND NAMES — Caverject Impulse®; Caverject®; Edex®; Muse®; Prostin VR Pediatric®

PHARMACOLOGIC CATEGORY
Prostaglandin
Vasodilator

DOSING: ADULTS
Erectile dysfunction:
Intracavernous (Caverject®, Edex®): Individualize dose by careful titration; doses >40 mcg (Edex®) or >60 mcg (Caverject®) are not recommended: Initial dose must be titrated in physician's office. Patient must stay in the physician's office until complete detumescence occurs; if there is no response, then the next higher dose may be given within 1 hour; if there is still no response, a 1-day interval before giving the next dose is recommended; increasing the dose or concentration in the treatment of impotence results in increasing pain and discomfort.
Vasculogenic, psychogenic, or mixed etiology: Initiate dosage titration at 2.5 mcg, increasing by 2.5 mcg to a dose of 5 mcg and then in increments of 5-10 mcg depending on the erectile response until the dose produces an erection suitable for intercourse, not lasting >1 hour; if there is absolutely no response to initial 2.5 mcg dose, the second dose may be increased to 7.5 mcg, followed by increments of 5-10 mcg
Neurogenic etiology (eg, spinal cord injury): Initiate dosage titration at 1.25 mcg, increasing to a dose of 2.5 mcg and then 5 mcg; increase further in increments 5 mcg until the dose is reached that produces an erection suitable for intercourse, not lasting >1 hour
Maintenance: Once appropriate dose has been determined, patient may self-administer injections at a frequency of no more than 3 times/week with at least 24 hours between doses
Intraurethral (Muse® Pellet):
Initial: 125-250 mcg
Maintenance: Administer as needed to achieve an erection; duration of action is about 30-60 minutes; use only two systems per 24-hour period

DOSING: PEDIATRIC

(For additional information see "Alprostadil: Pediatric drug information")
Patent ductus arteriosus I.V.:
Prostin VR Pediatric®: I.V. continuous infusion into a large vein, or alternatively through an umbilical artery catheter placed at the ductal opening: 0.05-0.1 mcg/kg/minute with therapeutic response, rate is reduced to lowest effective dosage. With unsatisfactory response, rate is increased gradually; maintenance: 0.01-0.4 mcg/kg/minute.
Note: PGE1 is usually given at an infusion rate of 0.1 mcg/kg/minute, but it is often possible to reduce the dosage to 1/2 or even 1/10 without losing the therapeutic effect. The mixing schedule is shown in the table.

Mixing Schedule

Note: 500 mcg equals 1 ampul. For a concentration of 2 mcg/mL, add 500 mcg to 250 mL; infuse at 0.05 mL/kg/minute (72 mL/kg/24 hours) For a concentration of 5 mcg/mL, add 500 mcg to 100 mL; infuse at 0.02 mL/kg/minute (28.8 mL/kg/24 hours) For a concentration of 10 mcg/mL, add 500 mcg to 50 mL; infuse at 0.01 mL/kg/minute (14.4 mL/kg/24 hours) For a concentration of 20 mcg/mL, add 500 mcg to 25 mL; infuse at 0.005 mL/kg/minute (7.2 mL/kg/24 hours)

Note: Therapeutic response is indicated by increased pH in those with acidosis or by an increase in oxygenation (PO2) usually evident within 30 minutes.

DOSING: ELDERLY — Elderly patients may have a greater frequency of renal dysfunction; lowest effective dose should be used. In clinical studies with Edex®, higher minimally effective doses and a higher rate of lack of effect were noted. dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injection, powder for reconstitution:
Caverject®: 20 mcg, 40 mcg [contains lactose; diluent contains benzyl alcohol]
Caverject Impulse®: 10 mcg, 20 mcg [prefilled injection system; contains lactose; diluent contains benzyl alcohol]
Edex®: 10 mcg, 20 mcg, 40 mcg [contains lactose; packaged in kits containing diluent, syringe, and alcohol swab]

Injection, solution: 500 mcg/mL (1 mL)
Prostin VR Pediatric®: 500 mcg/mL (1 mL) [contains dehydrated alcohol]

Pellet, urethral:
Muse®: 125 mcg (6s) [DSC], 250 mcg (6s), 500 mcg (6s), 1000 mcg (6s)

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Caverject®: 20 mcg, 40 mcg
Caverject Impulse®: 10 mcg, 20 mcg
Edex®: 10 mcg, 20 mcg, 40 mcg

Injection, solution: 500 mcg/mL (1 mL)
Prostin VR Pediatric®: 500 mcg/mL (1 mL)

Pellet, urethral:
Muse®: 250 mcg (6s), 500 mcg (6s), 1000 mcg (6s)

GENERIC EQUIVALENT AVAILABLE — Yes: Solution for injection

ADMINISTRATION — Erectile dysfunction: Use a 1/2 inch, 27- to 30-gauge needle. Inject into the dorsolateral aspect of the proximal third of the penis, avoiding visible veins; alternate side of the penis for injections.

USE
Prostin VR Pediatric®: Temporary maintenance of patency of ductus arteriosus in neonates with ductal-dependent congenital heart disease until surgery can be performed. These defects include cyanotic (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, Fallot's tetralogy, transposition of the great vessels) and acyanotic (eg, interruption of aortic arch, coarctation of aorta, hypoplastic left ventricle) heart disease.

Caverject®: Treatment of erectile dysfunction of vasculogenic, psychogenic, or neurogenic etiology; adjunct in the diagnosis of erectile dysfunction

Edex®, Muse®: Treatment of erectile dysfunction of vasculogenic, psychogenic, or neurogenic etiology

USE - UNLABELED / INVESTIGATIONAL — Investigational: Treatment of pulmonary hypertension in infants and children with congenital heart defects with left-to-right shunts

ADVERSE REACTIONS SIGNIFICANT
Intraurethral:

>10%: Genitourinary: Penile pain, urethral burning

2% to 10%:
Central nervous system: Headache, dizziness, pain
Genitourinary: Vaginal itching (female partner), testicular pain, urethral bleeding (minor)

<2% (Limited to important or life-threatening): Tachycardia, perineal pain, leg pain

Intracavernosal injection:

>10%: Genitourinary: Penile pain

1% to 10%:
Cardiovascular: Hypertension
Central nervous system: Headache, dizziness
Genitourinary: Prolonged erection (>4 hours, 4%), penile fibrosis, penis disorder, penile rash, penile edema
Local: Injection site hematoma and/or bruising

<1% (Limited to important or life-threatening): Balanitis, injection site hemorrhage, priapism (0.4%)

Intravenous:

>10%:
Cardiovascular: Flushing
Central nervous system: Fever
Respiratory: Apnea

1% to 10%:
Cardiovascular: Bradycardia, hyper-/hypotension, tachycardia, cardiac arrest, edema
Central nervous system: Seizure, headache, dizziness
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Diarrhea
Hematologic: Disseminated intravascular coagulation
Neuromuscular & skeletal: Back pain
Respiratory: Upper respiratory infection, flu syndrome, sinusitis, nasal congestion, cough
Miscellaneous: Sepsis, localized pain in structures other than the injection site

<1% (Limited to important or life-threatening): Anemia, anuria, bleeding, bradypnea, bronchial wheezing, cerebral bleeding, CHF, gastric regurgitation, hematuria, hyperbilirubinemia, hyperemia, hyperextension of neck, hyperirritability, hyperkalemia, hypoglycemia, hypothermia, jitteriness, lethargy, peritonitis, second-degree heart block, shock, stiffness, supraventricular tachycardia, thrombocytopenia, ventricular fibrillation

CONTRAINDICATIONS — Hypersensitivity to alprostadil or any component of the formulation; hyaline membrane disease or persistent fetal circulation and when a dominant left-to-right shunt is present; respiratory distress syndrome; conditions predisposing patients to priapism (sickle cell anemia, multiple myeloma, leukemia); patients with anatomical deformation of the penis, penile implants; use in men for whom sexual activity is inadvisable or contraindicated; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Apnea: .

Concerns related to adverse effects: Apnea: [U.S. Boxed Warning]: Apnea may occur in 10% to 12% of neonates with congenital heart defects, especially in those weighing <2 kg at birth. Apnea usually appears during the first hour of drug infusion.

Disease-related concerns: Erectile dysfunction: Appropriate use: When used in erectile dysfunction, priapism may occur; patient must be instructed to report to physician or seek immediate medical assistance if an erection persists for longer than 4 hours. Treat immediately to avoid penile tissue damage and permanent loss of potency; discontinue therapy if signs of penile fibrosis develop (penile angulation, cavernosal fibrosis, or Peyronie's disease). Patency of ductus arteriosus: Appropriate use: Infuse for the shortest time at the lowest dose consistent with good patient care. Use for >120 hours has been associated with antral hyperplasia and gastric outlet obstruction.

Special populations: Neonates: Use with caution in neonates with bleeding tendencies.

Dosage form specific issues: Muse®: When used in erectile dysfunction, syncope occurring within 1 hour of administration has been reported. The potential for drug-drug interactions may occur when prescribed concomitantly with antihypertensives. Some lowering of blood pressure may occur without symptoms, and swelling of leg veins, leg pain, perineal pain, and rapid pulse have been reported in <2% of patients during in-clinic titration and home treatment.

DRUG INTERACTIONS — There are no known significant interactions.

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid concurrent use (vasodilating effect).

PREGNANCY RISK FACTOR — X/C (show table) (Muse®)

PREGNANCY IMPLICATIONS — Alprostadil is embryotoxic in animal studies. It is not indicated for use in women. The manufacturer of Muse® recommends a condom barrier when being used during sexual intercourse with a pregnant women.

LACTATION — Not indicated for use in women

PRICING — (data from drugstore.com)
Kit (Caverject Impulse)
10 mcg (2): $71.43
20 mcg (2): $90.72

Kit (Edex)
10 mcg (1): $72.17
10 mcg (1): $204.41
20 mcg (1): $91.09
20 mcg (1): $246.76
40 mcg (1): $126.38
40 mcg (1): $338.44

Pellet (Muse)
125 mcg (6): $162.43
250 mcg (6): $169.11
500 mcg (6): $180.24
1000 mcg (6): $195.82

Solution (reconstituted) (Caverject)
20 mcg (6): $248.38
40 mcg (6): $291.57

MONITORING PARAMETERS — Arterial pressure, respiratory rate, heart rate, temperature, degree of penile pain, length of erection, signs of infection

CANADIAN BRAND NAMES — Caverject®; Muse® Pellet; Prostin® VR

INTERNATIONAL BRAND NAMES — Alostin (KP); Alprostapint (BG, HU, PL); Befar (HK); Caverject (AE, AR, AT, BB, BH, BM, BO, BR, BS, BZ, CN, CO, CR, CY, DE, DO, EC, EE, EG, FR, GB, GT, GY, HN, HU, IE, IL, IQ, IR, JM, JO, KW, LB, LU, LY, MX, MY, NI, NL, NO, NZ, OM, PA, PE, PL, PR, PT, PY, QA, SA, SE, SG, SR, SV, SY, TT, TW, UY, VE, YE, ZA); Caverject Dual Chamber (FR, HK); Caverject Impulse (AU); Caverjet (IL); Edex (FR, PL); Eglandin (KP); Gaverject (PK); Liple (JP); Lyple (JP); Minprog (AT); Muse (AE, BH, CY, EG, GB, IE, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE, ZA); Palux (JP); Prink (KP); Promostan (TW); Prostandin (JP, KP); Prostavasin (AR, BR, CL, HU, LU, PH, PL, UY); Prostin (CZ); Prostin Pediatrico (CN); Prostin VR (AE, AU, BE, BH, CH, CO, CY, EG, GB, GR, HN, HU, IL, IN, IQ, IR, IT, JO, KW, LB, LY, NL, OM, PL, QA, SA, SY, TH, TW, YE, ZA); Prostin VR Paedeatric (MY); Prostine VR (FR); Prostivas (DK, FI, NO, SE); Sugiran (ES); Viridal (DE)

MECHANISM OF ACTION — Causes vasodilation by means of direct effect on vascular and ductus arteriosus smooth muscle; relaxes trabecular smooth muscle by dilation of cavernosal arteries when injected along the penile shaft, allowing blood flow to and entrapment in the lacunar spaces of the penis (ie, corporeal veno-occlusive mechanism)

PHARMACODYNAMICS / KINETICS
Onset of action: Rapid

Duration: <1 hour

Distribution: Insignificant following penile injection

Protein binding, plasma: 81% to albumin

Metabolism: ~75% by oxidation in one pass via lungs

Half-life elimination: 5-10 minutes

Excretion: Urine (90% as metabolites) within 24 hours

PATIENT INFORMATION — Store in refrigerator; if self-injecting for the treatment of impotence, dilute with the supplied diluent and use immediately after diluting; see prescriber at least every 3 months to ensure proper technique and for dosage adjustment. Alternate sides of the penis with each injection; do not inject more than 3 times/week, allowing at least 24 hours between each dose; dispose of the syringe, needle, and vial properly; discard single-use vials after each use; report moderate to severe penile pain or erections lasting >4 hours to a prescriber immediately; inform a prescriber as soon as possible if any new penile pain, nodules, hard tissue, or signs of infection develop; the risk of transmission of blood-borne diseases is increased with use of alprostadil injections since a small amount of bleeding at the injection site is possible. Do not drive or operate heavy machinery within 1 hour of administration.

Alprostadil

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alprostadil may be confused with alPRAZolam

U.S. BRAND NAMES — Caverject Impulse®; Caverject®; Edex®; Muse®; Prostin VR Pediatric®

PHARMACOLOGIC CATEGORY
Prostaglandin
Vasodilator

DOSING: ADULTS
Erectile dysfunction:
Intracavernous (Caverject®, Edex®): Individualize dose by careful titration; doses >40 mcg (Edex®) or >60 mcg (Caverject®) are not recommended: Initial dose must be titrated in physician's office. Patient must stay in the physician's office until complete detumescence occurs; if there is no response, then the next higher dose may be given within 1 hour; if there is still no response, a 1-day interval before giving the next dose is recommended; increasing the dose or concentration in the treatment of impotence results in increasing pain and discomfort.
Vasculogenic, psychogenic, or mixed etiology: Initiate dosage titration at 2.5 mcg, increasing by 2.5 mcg to a dose of 5 mcg and then in increments of 5-10 mcg depending on the erectile response until the dose produces an erection suitable for intercourse, not lasting >1 hour; if there is absolutely no response to initial 2.5 mcg dose, the second dose may be increased to 7.5 mcg, followed by increments of 5-10 mcg
Neurogenic etiology (eg, spinal cord injury): Initiate dosage titration at 1.25 mcg, increasing to a dose of 2.5 mcg and then 5 mcg; increase further in increments 5 mcg until the dose is reached that produces an erection suitable for intercourse, not lasting >1 hour
Maintenance: Once appropriate dose has been determined, patient may self-administer injections at a frequency of no more than 3 times/week with at least 24 hours between doses
Intraurethral (Muse® Pellet):
Initial: 125-250 mcg
Maintenance: Administer as needed to achieve an erection; duration of action is about 30-60 minutes; use only two systems per 24-hour period

DOSING: PEDIATRIC

(For additional information see "Alprostadil: Pediatric drug information")
Patent ductus arteriosus I.V.:
Prostin VR Pediatric®: I.V. continuous infusion into a large vein, or alternatively through an umbilical artery catheter placed at the ductal opening: 0.05-0.1 mcg/kg/minute with therapeutic response, rate is reduced to lowest effective dosage. With unsatisfactory response, rate is increased gradually; maintenance: 0.01-0.4 mcg/kg/minute.
Note: PGE1 is usually given at an infusion rate of 0.1 mcg/kg/minute, but it is often possible to reduce the dosage to 1/2 or even 1/10 without losing the therapeutic effect. The mixing schedule is shown in the table.

Mixing Schedule

Note: 500 mcg equals 1 ampul. For a concentration of 2 mcg/mL, add 500 mcg to 250 mL; infuse at 0.05 mL/kg/minute (72 mL/kg/24 hours) For a concentration of 5 mcg/mL, add 500 mcg to 100 mL; infuse at 0.02 mL/kg/minute (28.8 mL/kg/24 hours) For a concentration of 10 mcg/mL, add 500 mcg to 50 mL; infuse at 0.01 mL/kg/minute (14.4 mL/kg/24 hours) For a concentration of 20 mcg/mL, add 500 mcg to 25 mL; infuse at 0.005 mL/kg/minute (7.2 mL/kg/24 hours)

Note: Therapeutic response is indicated by increased pH in those with acidosis or by an increase in oxygenation (PO2) usually evident within 30 minutes.

DOSING: ELDERLY — Elderly patients may have a greater frequency of renal dysfunction; lowest effective dose should be used. In clinical studies with Edex®, higher minimally effective doses and a higher rate of lack of effect were noted. dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injection, powder for reconstitution:
Caverject®: 20 mcg, 40 mcg [contains lactose; diluent contains benzyl alcohol]
Caverject Impulse®: 10 mcg, 20 mcg [prefilled injection system; contains lactose; diluent contains benzyl alcohol]
Edex®: 10 mcg, 20 mcg, 40 mcg [contains lactose; packaged in kits containing diluent, syringe, and alcohol swab]

Injection, solution: 500 mcg/mL (1 mL)
Prostin VR Pediatric®: 500 mcg/mL (1 mL) [contains dehydrated alcohol]

Pellet, urethral:
Muse®: 125 mcg (6s) [DSC], 250 mcg (6s), 500 mcg (6s), 1000 mcg (6s)

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Caverject®: 20 mcg, 40 mcg
Caverject Impulse®: 10 mcg, 20 mcg
Edex®: 10 mcg, 20 mcg, 40 mcg

Injection, solution: 500 mcg/mL (1 mL)
Prostin VR Pediatric®: 500 mcg/mL (1 mL)

Pellet, urethral:
Muse®: 250 mcg (6s), 500 mcg (6s), 1000 mcg (6s)

GENERIC EQUIVALENT AVAILABLE — Yes: Solution for injection

ADMINISTRATION — Erectile dysfunction: Use a 1/2 inch, 27- to 30-gauge needle. Inject into the dorsolateral aspect of the proximal third of the penis, avoiding visible veins; alternate side of the penis for injections.

USE
Prostin VR Pediatric®: Temporary maintenance of patency of ductus arteriosus in neonates with ductal-dependent congenital heart disease until surgery can be performed. These defects include cyanotic (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, Fallot's tetralogy, transposition of the great vessels) and acyanotic (eg, interruption of aortic arch, coarctation of aorta, hypoplastic left ventricle) heart disease.

Caverject®: Treatment of erectile dysfunction of vasculogenic, psychogenic, or neurogenic etiology; adjunct in the diagnosis of erectile dysfunction

Edex®, Muse®: Treatment of erectile dysfunction of vasculogenic, psychogenic, or neurogenic etiology

USE - UNLABELED / INVESTIGATIONAL — Investigational: Treatment of pulmonary hypertension in infants and children with congenital heart defects with left-to-right shunts

ADVERSE REACTIONS SIGNIFICANT
Intraurethral:

>10%: Genitourinary: Penile pain, urethral burning

2% to 10%:
Central nervous system: Headache, dizziness, pain
Genitourinary: Vaginal itching (female partner), testicular pain, urethral bleeding (minor)

<2% (Limited to important or life-threatening): Tachycardia, perineal pain, leg pain

Intracavernosal injection:

>10%: Genitourinary: Penile pain

1% to 10%:
Cardiovascular: Hypertension
Central nervous system: Headache, dizziness
Genitourinary: Prolonged erection (>4 hours, 4%), penile fibrosis, penis disorder, penile rash, penile edema
Local: Injection site hematoma and/or bruising

<1% (Limited to important or life-threatening): Balanitis, injection site hemorrhage, priapism (0.4%)

Intravenous:

>10%:
Cardiovascular: Flushing
Central nervous system: Fever
Respiratory: Apnea

1% to 10%:
Cardiovascular: Bradycardia, hyper-/hypotension, tachycardia, cardiac arrest, edema
Central nervous system: Seizure, headache, dizziness
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Diarrhea
Hematologic: Disseminated intravascular coagulation
Neuromuscular & skeletal: Back pain
Respiratory: Upper respiratory infection, flu syndrome, sinusitis, nasal congestion, cough
Miscellaneous: Sepsis, localized pain in structures other than the injection site

<1% (Limited to important or life-threatening): Anemia, anuria, bleeding, bradypnea, bronchial wheezing, cerebral bleeding, CHF, gastric regurgitation, hematuria, hyperbilirubinemia, hyperemia, hyperextension of neck, hyperirritability, hyperkalemia, hypoglycemia, hypothermia, jitteriness, lethargy, peritonitis, second-degree heart block, shock, stiffness, supraventricular tachycardia, thrombocytopenia, ventricular fibrillation

CONTRAINDICATIONS — Hypersensitivity to alprostadil or any component of the formulation; hyaline membrane disease or persistent fetal circulation and when a dominant left-to-right shunt is present; respiratory distress syndrome; conditions predisposing patients to priapism (sickle cell anemia, multiple myeloma, leukemia); patients with anatomical deformation of the penis, penile implants; use in men for whom sexual activity is inadvisable or contraindicated; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Apnea: .

Concerns related to adverse effects: Apnea: [U.S. Boxed Warning]: Apnea may occur in 10% to 12% of neonates with congenital heart defects, especially in those weighing <2 kg at birth. Apnea usually appears during the first hour of drug infusion.

Disease-related concerns: Erectile dysfunction: Appropriate use: When used in erectile dysfunction, priapism may occur; patient must be instructed to report to physician or seek immediate medical assistance if an erection persists for longer than 4 hours. Treat immediately to avoid penile tissue damage and permanent loss of potency; discontinue therapy if signs of penile fibrosis develop (penile angulation, cavernosal fibrosis, or Peyronie's disease). Patency of ductus arteriosus: Appropriate use: Infuse for the shortest time at the lowest dose consistent with good patient care. Use for >120 hours has been associated with antral hyperplasia and gastric outlet obstruction.

Special populations: Neonates: Use with caution in neonates with bleeding tendencies.

Dosage form specific issues: Muse®: When used in erectile dysfunction, syncope occurring within 1 hour of administration has been reported. The potential for drug-drug interactions may occur when prescribed concomitantly with antihypertensives. Some lowering of blood pressure may occur without symptoms, and swelling of leg veins, leg pain, perineal pain, and rapid pulse have been reported in <2% of patients during in-clinic titration and home treatment.

DRUG INTERACTIONS — There are no known significant interactions.

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid concurrent use (vasodilating effect).

PREGNANCY RISK FACTOR — X/C (show table) (Muse®)

PREGNANCY IMPLICATIONS — Alprostadil is embryotoxic in animal studies. It is not indicated for use in women. The manufacturer of Muse® recommends a condom barrier when being used during sexual intercourse with a pregnant women.

LACTATION — Not indicated for use in women

PRICING — (data from drugstore.com)
Kit (Caverject Impulse)
10 mcg (2): $71.43
20 mcg (2): $90.72

Kit (Edex)
10 mcg (1): $72.17
10 mcg (1): $204.41
20 mcg (1): $91.09
20 mcg (1): $246.76
40 mcg (1): $126.38
40 mcg (1): $338.44

Pellet (Muse)
125 mcg (6): $162.43
250 mcg (6): $169.11
500 mcg (6): $180.24
1000 mcg (6): $195.82

Solution (reconstituted) (Caverject)
20 mcg (6): $248.38
40 mcg (6): $291.57

MONITORING PARAMETERS — Arterial pressure, respiratory rate, heart rate, temperature, degree of penile pain, length of erection, signs of infection

CANADIAN BRAND NAMES — Caverject®; Muse® Pellet; Prostin® VR

INTERNATIONAL BRAND NAMES — Alostin (KP); Alprostapint (BG, HU, PL); Befar (HK); Caverject (AE, AR, AT, BB, BH, BM, BO, BR, BS, BZ, CN, CO, CR, CY, DE, DO, EC, EE, EG, FR, GB, GT, GY, HN, HU, IE, IL, IQ, IR, JM, JO, KW, LB, LU, LY, MX, MY, NI, NL, NO, NZ, OM, PA, PE, PL, PR, PT, PY, QA, SA, SE, SG, SR, SV, SY, TT, TW, UY, VE, YE, ZA); Caverject Dual Chamber (FR, HK); Caverject Impulse (AU); Caverjet (IL); Edex (FR, PL); Eglandin (KP); Gaverject (PK); Liple (JP); Lyple (JP); Minprog (AT); Muse (AE, BH, CY, EG, GB, IE, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE, ZA); Palux (JP); Prink (KP); Promostan (TW); Prostandin (JP, KP); Prostavasin (AR, BR, CL, HU, LU, PH, PL, UY); Prostin (CZ); Prostin Pediatrico (CN); Prostin VR (AE, AU, BE, BH, CH, CO, CY, EG, GB, GR, HN, HU, IL, IN, IQ, IR, IT, JO, KW, LB, LY, NL, OM, PL, QA, SA, SY, TH, TW, YE, ZA); Prostin VR Paedeatric (MY); Prostine VR (FR); Prostivas (DK, FI, NO, SE); Sugiran (ES); Viridal (DE)

MECHANISM OF ACTION — Causes vasodilation by means of direct effect on vascular and ductus arteriosus smooth muscle; relaxes trabecular smooth muscle by dilation of cavernosal arteries when injected along the penile shaft, allowing blood flow to and entrapment in the lacunar spaces of the penis (ie, corporeal veno-occlusive mechanism)

PHARMACODYNAMICS / KINETICS
Onset of action: Rapid

Duration: <1 hour

Distribution: Insignificant following penile injection

Protein binding, plasma: 81% to albumin

Metabolism: ~75% by oxidation in one pass via lungs

Half-life elimination: 5-10 minutes

Excretion: Urine (90% as metabolites) within 24 hours

PATIENT INFORMATION — Store in refrigerator; if self-injecting for the treatment of impotence, dilute with the supplied diluent and use immediately after diluting; see prescriber at least every 3 months to ensure proper technique and for dosage adjustment. Alternate sides of the penis with each injection; do not inject more than 3 times/week, allowing at least 24 hours between each dose; dispose of the syringe, needle, and vial properly; discard single-use vials after each use; report moderate to severe penile pain or erections lasting >4 hours to a prescriber immediately; inform a prescriber as soon as possible if any new penile pain, nodules, hard tissue, or signs of infection develop; the risk of transmission of blood-borne diseases is increased with use of alprostadil injections since a small amount of bleeding at the injection site is possible. Do not drive or operate heavy machinery within 1 hour of administration.

Alprazolam

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
ALPRAZolam may be confused with alprostadil, LORazepam, triazolam
Xanax® may be confused with Lanoxin®, Tenex®, Tylox®, Xopenex®, Zantac®, Zyrtec®

U.S. BRAND NAMES — Alprazolam Intensol®; Niravam™ ; Xanax XR®; Xanax®

PHARMACOLOGIC CATEGORY
Benzodiazepine

DOSING: ADULTS — Note: Treatment >4 months should be re-evaluated to determine the patient's continued need for the drug

Anxiety: Oral: Immediate release: Effective doses are 0.5-4 mg/day in divided doses; the manufacturer recommends starting at 0.25-0.5 mg 3 times/day; titrate dose upward; usual maximum: 4 mg/day. Patients requiring doses >4 mg/day should be increased cautiously. Periodic reassessment and consideration of dosage reduction is recommended.

Anxiety associated with depression: Oral: Immediate release: Average dose required: 2.5-3 mg/day in divided doses

Ethanol withdrawal (unlabeled use): Oral: Immediate release: Usual dose: 2-2.5 mg/day in divided doses

Panic disorder: Oral:
Immediate release: Initial: 0.5 mg 3 times/day; dose may be increased every 3-4 days in increments ≤ 1 mg/day. Mean effective dosage: 5-6 mg/day; many patients obtain relief at 2 mg/day, as much as 10 mg/day may be required
Extended release: 0.5-1 mg once daily; may increase dose every 3-4 days in increments ≤ 1 mg/day (range: 3-6 mg/day)
Switching from immediate release to extended release: Patients may be switched to extended release tablets by taking the total daily dose of the immediate release tablets and giving it once daily using the extended release preparation.

Preoperative sedation: Oral: 0.5 mg in evening at bedtime and 0.5 mg 1 hour before procedure

Dose reduction: Abrupt discontinuation should be avoided. Daily dose may be decreased by 0.5 mg every 3 days, however, some patients may require a slower reduction. If withdrawal symptoms occur, resume previous dose and discontinue on a less rapid schedule.

DOSING: PEDIATRIC

(For additional information see "Alprazolam: Pediatric drug information")
Anxiety (unlabeled use): Oral: Immediate release: Initial: 0.005 mg/kg/dose or 0.125 mg/dose 3 times/day; increase in increments of 0.125-0.25 mg, up to a maximum of 0.02 mg/kg/dose or 0.06 mg/kg/day (0.375-3 mg/day). See "Dose Reduction" comment in adult dosing.

Note: Treatment >4 months should be re-evaluated to determine the patient's continued need for the drug.

DOSING: ELDERLY — Initial: 0.125-0.25 mg twice daily; increase by 0.125 mg/day as needed. The smallest effective dose should be used.
Immediate release: Initial 0.25 mg 2-3 times/day
Extended release: Initial: 0.5 mg once daily

DOSING: RENAL IMPAIRMENT — No guidelines for adjustment; use caution.

DOSING: HEPATIC IMPAIRMENT — Oral: Reduce dose by 50% to 60% or avoid in cirrhosis.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, oral [concentrate]:
Alprazolam Intensol®: 1 mg/mL (30 mL) [alcohol free, dye free, sugar free; contains propylene glycol]

Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Xanax®: 0.25 mg, 0.5 mg, 1 mg, 2 mg

Tablet, extended release: 0.5 mg, 1 mg, 2 mg, 3 mg
Xanax XR®: 0.5 mg, 1 mg, 2 mg, 3 mg

Tablet, orally disintegrating [scored]: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Niravam™ : 0.25 mg, 0.5 mg, 1 mg, 2 mg [orange flavor]

DOSAGE FORMS: CONCISE
Solution, oral [concentrate]:
Alprazolam Intensol®: 1 mg/mL

Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Xanax®: 0.25 mg, 0.5 mg, 1 mg, 2 mg

Tablet, extended release: 0.5 mg, 1 mg, 2 mg, 3 mg
Xanax XR®: 0.5 mg, 1 mg, 2 mg, 3 mg

Tablet, orally disintegrating [scored]: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Niravam™ : 0.25 mg, 0.5 mg, 1 mg, 2 mg

GENERIC EQUIVALENT AVAILABLE — Yes: Excludes oral solution

ADMINISTRATION
Immediate release preparations: Can be administered sublingually with comparable onset and completeness of absorption.

Extended release tablet: Should be taken once daily in the morning; do not crush, break, or chew.

Orally-disintegrating tablets: Using dry hands, place tablet on top of tongue. If using one-half of tablet, immediately discard remaining half (may not remain stable). Administration with water is not necessary.

USE — Treatment of anxiety disorder (GAD); panic disorder, with or without agoraphobia; anxiety associated with depression

USE - UNLABELED / INVESTIGATIONAL — Anxiety in children

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Abnormal coordination, cognitive disorder, depression, drowsiness, fatigue, irritability, lightheadedness, memory impairment, sedation, somnolence
Gastrointestinal: Appetite increased/decreased, constipation, salivation decreased, weight gain/loss, xerostomia
Genitourinary: Micturition difficulty
Neuromuscular & skeletal: Dysarthria

1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Agitation, attention disturbance, confusion, depersonalization, derealization, disorientation, disinhibition, dizziness, dream abnormalities, fear, hallucinations, hypersomnia, nightmares, seizure, talkativeness
Dermatologic: Dermatitis, pruritus, rash
Endocrine & metabolic: Libido decreased/increased, menstrual disorders
Gastrointestinal: Salivation increased
Genitourinary: Incontinence
Hepatic: Bilirubin increased, jaundice, liver enzymes increased
Neuromuscular & skeletal: Arthralgia, ataxia, myalgia, paresthesia
Ocular: Diplopia
Respiratory: Allergic rhinitis, dyspnea

<1% (Limited to important or life-threatening): Amnesia, falls, galactorrhea, gynecomastia, hepatic failure, hepatitis, hyperprolactinemia, Stevens-Johnson syndrome

CONTRAINDICATIONS — Hypersensitivity to alprazolam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); narrow-angle glaucoma; concurrent use with ketoconazole or itraconazole; pregnancy

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia. CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.

Disease-related concerns: Depression: Use caution in patients with depression, particularly if suicidal risk may be present; episodes of mania or hypomania have occurred in depressed patients treated with alprazolam. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use (generally >10 days). Hepatic impairment: Use with caution in patients with hepatic impairment. Impaired gag reflux: Use with caution in patients with an impaired gag reflux. Renal impairment: Use with caution in patients with renal impairment or predisposition to urate nephropathy; has weak uricosuric properties. Respiratory disease: Use with caution in patients with respiratory disease.

Concurrent drug therapy issues: CNS depressants/psychoactive medications: Use with caution in patients receiving other CNS depressants or psychoactive medication; effects with other sedative drugs or ethanol may be potentiated. High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.

Special populations: Debilitated patients: Use with caution in debilitated patients. Elderly: Use with caution in the elderly; benzodiazepines have been associated with falls and traumatic injury. Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury. Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.

Other warnings/precautions: Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Breakthrough anxiety: At the end of dosing interval, breakthrough anxiety may occur. Withdrawal: Rebound or withdrawal symptoms, including seizures, may occur 18 hours to 3 days following abrupt discontinuation or large decreases in dose (more common in patients receiving >4 mg/day or prolonged treatment). Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

RESTRICTIONS — C-IV

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Clozapine: Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Disulfiram: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy

Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Oral Contraceptive (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Oral Contraceptive (Progestins): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: Amprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, and tipranavir are contraindicated with midazolam and triazolam according to each protease inhibitor's prescribing information. Risk D: Consider therapy modification

Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; Rabeprazole. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy

St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Cigarette smoking: May decrease alprazolam concentrations up to 50%.

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Alprazolam serum concentration is unlikely to be increased by grapefruit juice because of alprazolam's high oral bioavailability. The Cmax of the extended release formulation is increased by 25% when a high-fat meal is given 2 hours before dosing. Tmax is decreased 30% when food is given immediately prior to dose. Tmax is increased by 30% when food is given ≥ 1 hour after dose.

Herb/Nutraceutical: St John's wort may decrease alprazolam levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

PREGNANCY RISK FACTOR — D (show table)

PREGNANCY IMPLICATIONS — Benzodiazepines have the potential to cause harm to the fetus, particularly when administered during the first trimester. In addition, withdrawal symptoms may occur in the neonate following in utero exposure. Use during pregnancy should be avoided.

LACTATION — Enters breast milk/not recommended (AAP rates "of concern")

BREAST-FEEDING CONSIDERATIONS — Symptoms of withdrawal, lethargy, and loss of body weight have been reported in infants exposed to alprazolam and/or benzodiazepines while nursing. Breast-feeding is not recommended.

PRICING — (data from drugstore.com)
Concentrate (ALPRAZolam Intensol)
1 mg/mL (30): $67.03

Tablet, 24-hour (ALPRAZolam)
0.5 mg (30): $31.99
1 mg (30): $69.99
2 mg (30): $76.00
3 mg (30): $109.98

Tablet, 24-hour (Xanax XR)
0.5 mg (30): $81.58
1 mg (30): $104.06
2 mg (30): $135.16
3 mg (30): $202.73

Tablet, orally-disintegrating (Niravam)
0.25 mg (30): $86.32
0.5 mg (30): $104.93
1 mg (30): $135.40
2 mg (30): $213.26

Tablets (ALPRAZolam)
0.25 mg (30): $11.99
0.5 mg (30): $11.99
1 mg (30): $11.99
2 mg (30): $13.99

Tablets (Xanax)
0.25 mg (30): $48.29
0.5 mg (30): $54.01
1 mg (30): $68.34
2 mg (30): $111.29

MONITORING PARAMETERS — Respiratory and cardiovascular status

CANADIAN BRAND NAMES — Alti-Alprazolam; Apo-Alpraz®; Apo-Alpraz® TS; Gen-Alprazolam; Novo-Alprazol; Nu-Alprax; Xanax TS™ ; Xanax®

INTERNATIONAL BRAND NAMES — Aceprax (PY, UY); Actazolam (ID); Afobam (PL); Alcelam (TH); Alganax (ID); Alnax (TH); Alpaz (PE); Alplax (AR); Alpralid (IL); Alpraline (MY); Alpram (KP); Alpranax (MY); Alprax (AU, HK, IN, TH); Alpraz (LU); Alprazomerck (PL); Alprocontin (IN); Alprox (HU, IL, PL); Altrox (PH); Alviz (ID); Alzam (MX, ZA); Alzax (KP); Alzolam (IN); Anax (TH); Anpress (TH); Apo-Alpraz (SG); Apraz (BR); Aprazo (TW); Azor (ZA); Cassadan (DE); Constan (JP); Daclor (DO); Dixin (CO); Farmapram (MX); Feprax (ID); Frontal (BR); Frontin (HU, PL); Helex (HR); Irizz. (MX); Kalma (AU); Kinax (TW); Marzolam (TH); Neupax (MX); Neurol (PL); Pacyl (IN); Pharnax (TH); Prazol (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Prazovex (MY); Prinox (AR); Solanax (JP); Soxietas (ID); Tafil (CR, DE, DK, DO, GT, HN, MX, NI, PA, SV, VE); Tafil D (MU); Tazun (MX); Tensivan (CO); Trankimazin Retard (ES); Tranquinal (BR, DO, EC, GT, HN, NI, PA, PE, PY, SV, UY); Tricalma (CN); Valeans (IT); Xanacine (TH); Xanagis (IL); Xanax (AE, AR, AU, BB, BE, BF, BG, BH, BJ, BM, BS, BZ, CH, CI, CO, CY, CZ, DE, EC, EE, EG, ET, FR, GB, GH, GM, GN, GR, GY, HK, HN, HR, HU, IE, IL, IQ, IR, IT, JM, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MY, NE, NG, NL, OM, PE, PK, PL, PT, QA, SA, SC, SD, SL, SN, SR, SY, TH, TN, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Xanax SR (SG); Xanax XR (IL, TH, TW); Xanor (AT, FI, NO, PH, SE, ZA); Xanor XR (PH); Zacetin (KP); Zamhexal (AU); Zanapam (AE, BH, CY, EG, IL, IQ, IR, JO, KP, KW, LB, LY, OM, QA, SA, SY, YE); Zolam (IN); Zolarem (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZA, ZM, ZW); Zolastin (ID); Zoldac (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Zomiren (PL); Zopax (ZA); Zotran (CN); Zypraz (ID); Zyren (KP)

MECHANISM OF ACTION — Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.

PHARMACODYNAMICS / KINETICS
Onset of action: Immediate release and extended release formulations: 1 hour

Duration: Immediate release: 5.1 +/- 1.7 hours; Extended release: 11.3 +/- 4.2 hours

Absorption: Extended release: Slower relative to immediate release formulation resulting in a concentration that is maintained 5-11 hours after dosing

Distribution: Vd: 0.9-1.2 L/kg; enters breast milk

Protein binding: 80%; primarily to albumin

Metabolism: Hepatic via CYP3A4; forms two active metabolites (4-hydroxyalprazolam and alpha-hydroxyalprazolam)

Bioavailability: 90%

Half-life elimination:
Adults: 11.2 hours (immediate release range: 6.3-26.9; extended release range: 10.7-15.8)
Elderly: 16.3 hours (range: 9-26.9 hours)
Alcoholic liver disease: 19.7 hours (range: 5.8-65.3 hours)
Obesity: 21.8 hours (range: 9.9-40.4 hours)

Time to peak, serum: Immediate release: 1-2 hours; Extended release: ~9 hours; decreased by 1 hour following bedtime dosing compared to morning dosing

Excretion: Urine (as unchanged drug and metabolites)

PATIENT INFORMATION — Avoid alcohol and other CNS depressants; avoid activities needing good psychomotor coordination until CNS effects are known; drug may cause physical or psychological dependence; avoid abrupt discontinuation after prolonged use; do not crush, break, or chew extended release tablets