MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Anagrelide may be confused with anastrozole
U.S. BRAND NAMES — Agrylin®
PHARMACOLOGIC CATEGORY
Phospholipase A2 Inhibitor
DOSING: ADULTS — Thrombocythemia: Oral: Initial: 0.5 mg 4 times/day or 1 mg twice daily (most patients will experience adequate response at dose ranges of 1.5-3 mg/day)
Note: Maintain initial dose for ≥ 1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/µl>0.5 mg/day in any 1 week; maximum dose: 10 mg/day or 2.5 mg/dose
DOSING: PEDIATRIC — Thrombocythemia: Oral: Initial: 0.5 mg/day (range: 0.5 mg 1-4 times/day); see "Note" in adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — No adjustment required in renal insufficiency.
DOSING: HEPATIC IMPAIRMENT
Moderate impairment: Initial: 0.5 mg once daily; maintain for at least 1 week with careful monitoring of cardiovascular status; the dose must not be increased by >0.5 mg/day in any 1 week.
Severe impairment: Contraindicated
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
DOSAGE FORMS: CONCISE
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to food.
USE — Treatment of thrombocythemia associated with myeloproliferative disorders (eg, chronic myelogenous leukemia, essential thrombocythemia, polycythemia vera, myeloid metaplasia with myelofibrosis, or other myeloproliferative disorder)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Palpitation (26%), edema (21%)
Central nervous system: Headache (44%), dizziness (15%), pain (15%)
Gastrointestinal: Diarrhea (26%), nausea (17%), abdominal pain (16%)
Neuromuscular & skeletal: Weakness (23%)
Respiratory: Dyspnea (12%)
1% to 10%:
Cardiovascular: Peripheral edema (9%), chest pain (8%), tachycardia (8%), angina, arrhythmia, HF, hypertension, postural hypotension, syncope, thrombosis, vasodilatation
Central nervous system: Fever (9%), malaise (6%), amnesia, chills, confusion, depression, insomnia, migraine, nervousness, somnolence
Dermatologic: Rash (8%), pruritus (6%), alopecia, bruising, photosensitivity, urticaria
Endocrine & skeletal: Dehydration
Gastrointestinal: Flatulence (10%), vomiting (10%), anorexia (8%), dyspepsia (5%), aphthous stomatitis, constipation, eructation, gastritis, GI distress, GI hemorrhage, melena
Genitourinary: Dysuria
Hematologic: Thrombocytopenia (9%; grades 3/4: 5%), anemia, hemorrhage
Hepatic: Liver enzymes increased
Neuromuscular & skeletal: Back pain (6%), paresthesia (6%), arthralgia, leg cramps, myalgia
Ocular: Amblyopia, diplopia, visual field abnormality
Otic: Tinnitus
Renal: Renal abnormality (1% to <5%), renal failure (1%), hematuria
Respiratory: Pharyngitis (7%), cough (6%), asthma, bronchitis, epistaxis, pneumonia, rhinitis, sinusitis
Miscellaneous: Flu-like syndrome, lymphadenopathy
Frequency not defined: Atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete heart block, deep vein thrombosis, gastric/duodenal ulceration; interstitial lung disease (allergic alveolitis, eosinophilic pneumonia, interstitial pneumonitis); leukocyte count increased, MI, myelofibrosis, pancreatitis, pericarditis, pericardial effusion, pleural effusion, polycythemia, pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, seizure, stroke, transient ischemic attack
CONTRAINDICATIONS — Severe hepatic impairment
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Pulmonary disorders: Interstitial lung disease (including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis) has been associated with use. Onset is from 1 week to several years, usually presenting with progressive dyspnea with lung infiltrations; symptoms usually improve after discontinuation. Renal abnormalities: Renal abnormalities (including renal failure) have been observed with anagrelide use; may be associated with pre-existing renal impairment, although dosage adjustment due to renal insufficiency was not required. Monitor closely in patients with renal insufficiency.
Disease-related concerns: Cardiovascular disease: Use with caution in patients with known or suspected heart disease; tachycardia, orthostatic hypotension, and heart failure have been reported. Pretreatment cardiovascular evaluation and careful monitoring during treatment is recommended. Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment; dosage reduction and careful cardiovascular monitoring are required for moderate impairment; use is contraindicated in severe hepatic impairment.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor)
DRUG INTERACTIONS
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Drotrecogin Alfa: Antiplatelet 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 Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: May increase CNS adverse effects.
Food: No clinically significant effect on absorption.
Herb/Nutraceutical: Avoid herbs with anticoagulant/antiplatelet properties (alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng [American], ginseng [Panax], ginseng [Siberian], grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe [S-adenosylmethionine], sweet clover, turmeric, white willow); may enhance the adverse effect of antiplatelets agents.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies; however, decreased pup survival was noted. Use of anagrelide during pregnancy is limited. The manufacturer recommends effective contraception in women of childbearing potential. Use during pregnancy only if potential benefit to mother outweighs possible risk to the fetus.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken without regard to food.
PRICING — (data from drugstore.com)
Capsules (Agrylin)
0.5 mg (50): $270.99
1 mg (50): $546.00
Capsules (Anagrelide HCl)
0.5 mg (30): $79.55
1 mg (50): $100.00
MONITORING PARAMETERS — Platelet count (every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached); CBC with differential, ALT, AST, BUN, and serum creatinine (monitor closely during first weeks of treatment); blood pressure; cardiovascular exam (pretreatment; monitor during therapy). Monitor for thrombosis or bleeding.
CANADIAN BRAND NAMES — Agrylin®; Dom-Anagrelide; Mylan-Anagrelide; PHL-Anagrelide; PMS-Anagrelide; Sandoz-Anagrelide
INTERNATIONAL BRAND NAMES — Agrelid (AR); Agrylin (AU, HK, ID, IL, KP, PH, TW); Thromboreductin (HK, ID, MY); Xagrid (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Anagrelide appears to inhibit cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. It also causes a dose-related reduction in platelet production, which results from decreased megakaryocyte hypermaturation (disrupts the postmitotic phase of maturation).
PHARMACODYNAMICS / KINETICS
Onset of action: Initial: Within 7-14 days; complete response (platelets ≤ 600,000/mm3): 4-12 weeks
Duration: 6-24 hours; upon discontinuation, platelet count begins to rise within 4 days
Metabolism: Hepatic; to RL603 and 3-hydroxy anagrelide
Half-life elimination, plasma: 1.3 hours
Time to peak, serum: 1 hour
Excretion: Urine (<1% as unchanged drug)
Monday, August 2, 2010
Amyl nitrite
PHARMACOLOGIC CATEGORY
Antidote
Vasodilator
DOSING: ADULTS
Angina: Inhalation: 1-6 inhalations from 1 crushed ampul; may repeat in 3-5 minutes
Cyanide poisoning: Inhalation: Inhale the vapor from a 0.3 mL crushed ampul every minute for 15-30 seconds until I.V. sodium nitrite infusion is available
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
DOSAGE FORMS: CONCISE
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer nasally. Patient should not be sitting. Crush ampul in woven covering between fingers and then hold under patient's nostrils.
USE — Coronary vasodilator in angina pectoris; adjunct in treatment of cyanide poisoning; produce changes in the intensity of heart murmurs
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Postural hypotension, cutaneous flushing of head, neck, and clavicular area, palpitations, tachycardia, sinus tachycardia, vasodilation
Central nervous system: Headache, incoherent speech, restlessness
Dermatologic: Contact dermatitis
Gastrointestinal: Nausea, colitis, vomiting
Genitourinary: Penile erection enhanced, retarded ejaculation
Hematologic: Heinz body hemolysis/hemolytic anemia
Ocular: Increased intraocular pressure, blurred vision
Respiratory: Tracheobronchitis
CONTRAINDICATIONS — Hypersensitivity to nitrates; severe anemia; head injury; angle-closure glaucoma; postural hypotension; head trauma or cerebral hemorrhage; pregnancy
WARNINGS / PRECAUTIONS
Disease-related concerns: Cardiovascular disease: Use with caution in patients with coronary artery disease and patients with hypotension. Increased intracranial pressure: Use with caution in patients with increased intracranial pressure.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
LACTATION — Excretion in breast milk unknown/not recommended
MONITORING PARAMETERS — Monitor blood pressure during therapy
INTERNATIONAL BRAND NAMES — Amyl Nitrite (NZ)
MECHANISM OF ACTION — Relaxes vascular smooth muscle; decreased venous ratios and arterial blood pressure; reduces left ventricular work; decreases myocardial O2 consumption; in cyanide poisoning, amyl nitrite converts hemoglobin to methemoglobin that binds with cyanide to form cyanate hemoglobin
PHARMACODYNAMICS / KINETICS
Onset of action: Angina: Within 30 seconds
Duration: 3-15 minutes
PATIENT INFORMATION — Lie down during administration. Crush ampul between fingers and then inhale through nostrils. May cause dizziness. Call paramedics or have someone take you to the hospital immediately if pain is not relieved after 3 doses.
Antidote
Vasodilator
DOSING: ADULTS
Angina: Inhalation: 1-6 inhalations from 1 crushed ampul; may repeat in 3-5 minutes
Cyanide poisoning: Inhalation: Inhale the vapor from a 0.3 mL crushed ampul every minute for 15-30 seconds until I.V. sodium nitrite infusion is available
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
DOSAGE FORMS: CONCISE
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer nasally. Patient should not be sitting. Crush ampul in woven covering between fingers and then hold under patient's nostrils.
USE — Coronary vasodilator in angina pectoris; adjunct in treatment of cyanide poisoning; produce changes in the intensity of heart murmurs
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Postural hypotension, cutaneous flushing of head, neck, and clavicular area, palpitations, tachycardia, sinus tachycardia, vasodilation
Central nervous system: Headache, incoherent speech, restlessness
Dermatologic: Contact dermatitis
Gastrointestinal: Nausea, colitis, vomiting
Genitourinary: Penile erection enhanced, retarded ejaculation
Hematologic: Heinz body hemolysis/hemolytic anemia
Ocular: Increased intraocular pressure, blurred vision
Respiratory: Tracheobronchitis
CONTRAINDICATIONS — Hypersensitivity to nitrates; severe anemia; head injury; angle-closure glaucoma; postural hypotension; head trauma or cerebral hemorrhage; pregnancy
WARNINGS / PRECAUTIONS
Disease-related concerns: Cardiovascular disease: Use with caution in patients with coronary artery disease and patients with hypotension. Increased intracranial pressure: Use with caution in patients with increased intracranial pressure.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
LACTATION — Excretion in breast milk unknown/not recommended
MONITORING PARAMETERS — Monitor blood pressure during therapy
INTERNATIONAL BRAND NAMES — Amyl Nitrite (NZ)
MECHANISM OF ACTION — Relaxes vascular smooth muscle; decreased venous ratios and arterial blood pressure; reduces left ventricular work; decreases myocardial O2 consumption; in cyanide poisoning, amyl nitrite converts hemoglobin to methemoglobin that binds with cyanide to form cyanate hemoglobin
PHARMACODYNAMICS / KINETICS
Onset of action: Angina: Within 30 seconds
Duration: 3-15 minutes
PATIENT INFORMATION — Lie down during administration. Crush ampul between fingers and then inhale through nostrils. May cause dizziness. Call paramedics or have someone take you to the hospital immediately if pain is not relieved after 3 doses.
Anagrelide
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Anagrelide may be confused with anastrozole
U.S. BRAND NAMES — Agrylin®
PHARMACOLOGIC CATEGORY
Phospholipase A2 Inhibitor
DOSING: ADULTS — Thrombocythemia: Oral: Initial: 0.5 mg 4 times/day or 1 mg twice daily (most patients will experience adequate response at dose ranges of 1.5-3 mg/day)
Note: Maintain initial dose for ≥ 1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/µl>0.5 mg/day in any 1 week; maximum dose: 10 mg/day or 2.5 mg/dose
DOSING: PEDIATRIC — Thrombocythemia: Oral: Initial: 0.5 mg/day (range: 0.5 mg 1-4 times/day); see "Note" in adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — No adjustment required in renal insufficiency.
DOSING: HEPATIC IMPAIRMENT
Moderate impairment: Initial: 0.5 mg once daily; maintain for at least 1 week with careful monitoring of cardiovascular status; the dose must not be increased by >0.5 mg/day in any 1 week.
Severe impairment: Contraindicated
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
DOSAGE FORMS: CONCISE
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to food.
USE — Treatment of thrombocythemia associated with myeloproliferative disorders (eg, chronic myelogenous leukemia, essential thrombocythemia, polycythemia vera, myeloid metaplasia with myelofibrosis, or other myeloproliferative disorder)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Palpitation (26%), edema (21%)
Central nervous system: Headache (44%), dizziness (15%), pain (15%)
Gastrointestinal: Diarrhea (26%), nausea (17%), abdominal pain (16%)
Neuromuscular & skeletal: Weakness (23%)
Respiratory: Dyspnea (12%)
1% to 10%:
Cardiovascular: Peripheral edema (9%), chest pain (8%), tachycardia (8%), angina, arrhythmia, HF, hypertension, postural hypotension, syncope, thrombosis, vasodilatation
Central nervous system: Fever (9%), malaise (6%), amnesia, chills, confusion, depression, insomnia, migraine, nervousness, somnolence
Dermatologic: Rash (8%), pruritus (6%), alopecia, bruising, photosensitivity, urticaria
Endocrine & skeletal: Dehydration
Gastrointestinal: Flatulence (10%), vomiting (10%), anorexia (8%), dyspepsia (5%), aphthous stomatitis, constipation, eructation, gastritis, GI distress, GI hemorrhage, melena
Genitourinary: Dysuria
Hematologic: Thrombocytopenia (9%; grades 3/4: 5%), anemia, hemorrhage
Hepatic: Liver enzymes increased
Neuromuscular & skeletal: Back pain (6%), paresthesia (6%), arthralgia, leg cramps, myalgia
Ocular: Amblyopia, diplopia, visual field abnormality
Otic: Tinnitus
Renal: Renal abnormality (1% to <5%), renal failure (1%), hematuria
Respiratory: Pharyngitis (7%), cough (6%), asthma, bronchitis, epistaxis, pneumonia, rhinitis, sinusitis
Miscellaneous: Flu-like syndrome, lymphadenopathy
Frequency not defined: Atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete heart block, deep vein thrombosis, gastric/duodenal ulceration; interstitial lung disease (allergic alveolitis, eosinophilic pneumonia, interstitial pneumonitis); leukocyte count increased, MI, myelofibrosis, pancreatitis, pericarditis, pericardial effusion, pleural effusion, polycythemia, pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, seizure, stroke, transient ischemic attack
CONTRAINDICATIONS — Severe hepatic impairment
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Pulmonary disorders: Interstitial lung disease (including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis) has been associated with use. Onset is from 1 week to several years, usually presenting with progressive dyspnea with lung infiltrations; symptoms usually improve after discontinuation. Renal abnormalities: Renal abnormalities (including renal failure) have been observed with anagrelide use; may be associated with pre-existing renal impairment, although dosage adjustment due to renal insufficiency was not required. Monitor closely in patients with renal insufficiency.
Disease-related concerns: Cardiovascular disease: Use with caution in patients with known or suspected heart disease; tachycardia, orthostatic hypotension, and heart failure have been reported. Pretreatment cardiovascular evaluation and careful monitoring during treatment is recommended. Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment; dosage reduction and careful cardiovascular monitoring are required for moderate impairment; use is contraindicated in severe hepatic impairment.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor)
DRUG INTERACTIONS
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Drotrecogin Alfa: Antiplatelet 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 Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: May increase CNS adverse effects.
Food: No clinically significant effect on absorption.
Herb/Nutraceutical: Avoid herbs with anticoagulant/antiplatelet properties (alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng [American], ginseng [Panax], ginseng [Siberian], grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe [S-adenosylmethionine], sweet clover, turmeric, white willow); may enhance the adverse effect of antiplatelets agents.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies; however, decreased pup survival was noted. Use of anagrelide during pregnancy is limited. The manufacturer recommends effective contraception in women of childbearing potential. Use during pregnancy only if potential benefit to mother outweighs possible risk to the fetus.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken without regard to food.
PRICING — (data from drugstore.com)
Capsules (Agrylin)
0.5 mg (50): $270.99
1 mg (50): $546.00
Capsules (Anagrelide HCl)
0.5 mg (30): $79.55
1 mg (50): $100.00
MONITORING PARAMETERS — Platelet count (every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached); CBC with differential, ALT, AST, BUN, and serum creatinine (monitor closely during first weeks of treatment); blood pressure; cardiovascular exam (pretreatment; monitor during therapy). Monitor for thrombosis or bleeding.
CANADIAN BRAND NAMES — Agrylin®; Dom-Anagrelide; Mylan-Anagrelide; PHL-Anagrelide; PMS-Anagrelide; Sandoz-Anagrelide
INTERNATIONAL BRAND NAMES — Agrelid (AR); Agrylin (AU, HK, ID, IL, KP, PH, TW); Thromboreductin (HK, ID, MY); Xagrid (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Anagrelide appears to inhibit cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. It also causes a dose-related reduction in platelet production, which results from decreased megakaryocyte hypermaturation (disrupts the postmitotic phase of maturation).
PHARMACODYNAMICS / KINETICS
Onset of action: Initial: Within 7-14 days; complete response (platelets ≤ 600,000/mm3): 4-12 weeks
Duration: 6-24 hours; upon discontinuation, platelet count begins to rise within 4 days
Metabolism: Hepatic; to RL603 and 3-hydroxy anagrelide
Half-life elimination, plasma: 1.3 hours
Time to peak, serum: 1 hour
Excretion: Urine (<1% as unchanged drug)
Sound-alike/look-alike issues:
Anagrelide may be confused with anastrozole
U.S. BRAND NAMES — Agrylin®
PHARMACOLOGIC CATEGORY
Phospholipase A2 Inhibitor
DOSING: ADULTS — Thrombocythemia: Oral: Initial: 0.5 mg 4 times/day or 1 mg twice daily (most patients will experience adequate response at dose ranges of 1.5-3 mg/day)
Note: Maintain initial dose for ≥ 1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/µl>0.5 mg/day in any 1 week; maximum dose: 10 mg/day or 2.5 mg/dose
DOSING: PEDIATRIC — Thrombocythemia: Oral: Initial: 0.5 mg/day (range: 0.5 mg 1-4 times/day); see "Note" in adult dosing.
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — No adjustment required in renal insufficiency.
DOSING: HEPATIC IMPAIRMENT
Moderate impairment: Initial: 0.5 mg once daily; maintain for at least 1 week with careful monitoring of cardiovascular status; the dose must not be increased by >0.5 mg/day in any 1 week.
Severe impairment: Contraindicated
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
DOSAGE FORMS: CONCISE
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to food.
USE — Treatment of thrombocythemia associated with myeloproliferative disorders (eg, chronic myelogenous leukemia, essential thrombocythemia, polycythemia vera, myeloid metaplasia with myelofibrosis, or other myeloproliferative disorder)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Palpitation (26%), edema (21%)
Central nervous system: Headache (44%), dizziness (15%), pain (15%)
Gastrointestinal: Diarrhea (26%), nausea (17%), abdominal pain (16%)
Neuromuscular & skeletal: Weakness (23%)
Respiratory: Dyspnea (12%)
1% to 10%:
Cardiovascular: Peripheral edema (9%), chest pain (8%), tachycardia (8%), angina, arrhythmia, HF, hypertension, postural hypotension, syncope, thrombosis, vasodilatation
Central nervous system: Fever (9%), malaise (6%), amnesia, chills, confusion, depression, insomnia, migraine, nervousness, somnolence
Dermatologic: Rash (8%), pruritus (6%), alopecia, bruising, photosensitivity, urticaria
Endocrine & skeletal: Dehydration
Gastrointestinal: Flatulence (10%), vomiting (10%), anorexia (8%), dyspepsia (5%), aphthous stomatitis, constipation, eructation, gastritis, GI distress, GI hemorrhage, melena
Genitourinary: Dysuria
Hematologic: Thrombocytopenia (9%; grades 3/4: 5%), anemia, hemorrhage
Hepatic: Liver enzymes increased
Neuromuscular & skeletal: Back pain (6%), paresthesia (6%), arthralgia, leg cramps, myalgia
Ocular: Amblyopia, diplopia, visual field abnormality
Otic: Tinnitus
Renal: Renal abnormality (1% to <5%), renal failure (1%), hematuria
Respiratory: Pharyngitis (7%), cough (6%), asthma, bronchitis, epistaxis, pneumonia, rhinitis, sinusitis
Miscellaneous: Flu-like syndrome, lymphadenopathy
Frequency not defined: Atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete heart block, deep vein thrombosis, gastric/duodenal ulceration; interstitial lung disease (allergic alveolitis, eosinophilic pneumonia, interstitial pneumonitis); leukocyte count increased, MI, myelofibrosis, pancreatitis, pericarditis, pericardial effusion, pleural effusion, polycythemia, pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, seizure, stroke, transient ischemic attack
CONTRAINDICATIONS — Severe hepatic impairment
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Pulmonary disorders: Interstitial lung disease (including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis) has been associated with use. Onset is from 1 week to several years, usually presenting with progressive dyspnea with lung infiltrations; symptoms usually improve after discontinuation. Renal abnormalities: Renal abnormalities (including renal failure) have been observed with anagrelide use; may be associated with pre-existing renal impairment, although dosage adjustment due to renal insufficiency was not required. Monitor closely in patients with renal insufficiency.
Disease-related concerns: Cardiovascular disease: Use with caution in patients with known or suspected heart disease; tachycardia, orthostatic hypotension, and heart failure have been reported. Pretreatment cardiovascular evaluation and careful monitoring during treatment is recommended. Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment; dosage reduction and careful cardiovascular monitoring are required for moderate impairment; use is contraindicated in severe hepatic impairment.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor)
DRUG INTERACTIONS
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Drotrecogin Alfa: Antiplatelet 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 Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: May increase CNS adverse effects.
Food: No clinically significant effect on absorption.
Herb/Nutraceutical: Avoid herbs with anticoagulant/antiplatelet properties (alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng [American], ginseng [Panax], ginseng [Siberian], grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe [S-adenosylmethionine], sweet clover, turmeric, white willow); may enhance the adverse effect of antiplatelets agents.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies; however, decreased pup survival was noted. Use of anagrelide during pregnancy is limited. The manufacturer recommends effective contraception in women of childbearing potential. Use during pregnancy only if potential benefit to mother outweighs possible risk to the fetus.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken without regard to food.
PRICING — (data from drugstore.com)
Capsules (Agrylin)
0.5 mg (50): $270.99
1 mg (50): $546.00
Capsules (Anagrelide HCl)
0.5 mg (30): $79.55
1 mg (50): $100.00
MONITORING PARAMETERS — Platelet count (every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached); CBC with differential, ALT, AST, BUN, and serum creatinine (monitor closely during first weeks of treatment); blood pressure; cardiovascular exam (pretreatment; monitor during therapy). Monitor for thrombosis or bleeding.
CANADIAN BRAND NAMES — Agrylin®; Dom-Anagrelide; Mylan-Anagrelide; PHL-Anagrelide; PMS-Anagrelide; Sandoz-Anagrelide
INTERNATIONAL BRAND NAMES — Agrelid (AR); Agrylin (AU, HK, ID, IL, KP, PH, TW); Thromboreductin (HK, ID, MY); Xagrid (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Anagrelide appears to inhibit cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. It also causes a dose-related reduction in platelet production, which results from decreased megakaryocyte hypermaturation (disrupts the postmitotic phase of maturation).
PHARMACODYNAMICS / KINETICS
Onset of action: Initial: Within 7-14 days; complete response (platelets ≤ 600,000/mm3): 4-12 weeks
Duration: 6-24 hours; upon discontinuation, platelet count begins to rise within 4 days
Metabolism: Hepatic; to RL603 and 3-hydroxy anagrelide
Half-life elimination, plasma: 1.3 hours
Time to peak, serum: 1 hour
Excretion: Urine (<1% as unchanged drug)
Amyl nitrite
PHARMACOLOGIC CATEGORY
Antidote
Vasodilator
DOSING: ADULTS
Angina: Inhalation: 1-6 inhalations from 1 crushed ampul; may repeat in 3-5 minutes
Cyanide poisoning: Inhalation: Inhale the vapor from a 0.3 mL crushed ampul every minute for 15-30 seconds until I.V. sodium nitrite infusion is available
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
DOSAGE FORMS: CONCISE
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer nasally. Patient should not be sitting. Crush ampul in woven covering between fingers and then hold under patient's nostrils.
USE — Coronary vasodilator in angina pectoris; adjunct in treatment of cyanide poisoning; produce changes in the intensity of heart murmurs
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Postural hypotension, cutaneous flushing of head, neck, and clavicular area, palpitations, tachycardia, sinus tachycardia, vasodilation
Central nervous system: Headache, incoherent speech, restlessness
Dermatologic: Contact dermatitis
Gastrointestinal: Nausea, colitis, vomiting
Genitourinary: Penile erection enhanced, retarded ejaculation
Hematologic: Heinz body hemolysis/hemolytic anemia
Ocular: Increased intraocular pressure, blurred vision
Respiratory: Tracheobronchitis
CONTRAINDICATIONS — Hypersensitivity to nitrates; severe anemia; head injury; angle-closure glaucoma; postural hypotension; head trauma or cerebral hemorrhage; pregnancy
WARNINGS / PRECAUTIONS
Disease-related concerns: Cardiovascular disease: Use with caution in patients with coronary artery disease and patients with hypotension. Increased intracranial pressure: Use with caution in patients with increased intracranial pressure.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
LACTATION — Excretion in breast milk unknown/not recommended
MONITORING PARAMETERS — Monitor blood pressure during therapy
INTERNATIONAL BRAND NAMES — Amyl Nitrite (NZ)
MECHANISM OF ACTION — Relaxes vascular smooth muscle; decreased venous ratios and arterial blood pressure; reduces left ventricular work; decreases myocardial O2 consumption; in cyanide poisoning, amyl nitrite converts hemoglobin to methemoglobin that binds with cyanide to form cyanate hemoglobin
PHARMACODYNAMICS / KINETICS
Onset of action: Angina: Within 30 seconds
Duration: 3-15 minutes
PATIENT INFORMATION — Lie down during administration. Crush ampul between fingers and then inhale through nostrils. May cause dizziness. Call paramedics or have someone take you to the hospital immediately if pain is not relieved after 3 doses.
Antidote
Vasodilator
DOSING: ADULTS
Angina: Inhalation: 1-6 inhalations from 1 crushed ampul; may repeat in 3-5 minutes
Cyanide poisoning: Inhalation: Inhale the vapor from a 0.3 mL crushed ampul every minute for 15-30 seconds until I.V. sodium nitrite infusion is available
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
DOSAGE FORMS: CONCISE
Vapor for inhalation [crushable covered glass capsules]: Amyl nitrite USP (0.3 mL)
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer nasally. Patient should not be sitting. Crush ampul in woven covering between fingers and then hold under patient's nostrils.
USE — Coronary vasodilator in angina pectoris; adjunct in treatment of cyanide poisoning; produce changes in the intensity of heart murmurs
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Postural hypotension, cutaneous flushing of head, neck, and clavicular area, palpitations, tachycardia, sinus tachycardia, vasodilation
Central nervous system: Headache, incoherent speech, restlessness
Dermatologic: Contact dermatitis
Gastrointestinal: Nausea, colitis, vomiting
Genitourinary: Penile erection enhanced, retarded ejaculation
Hematologic: Heinz body hemolysis/hemolytic anemia
Ocular: Increased intraocular pressure, blurred vision
Respiratory: Tracheobronchitis
CONTRAINDICATIONS — Hypersensitivity to nitrates; severe anemia; head injury; angle-closure glaucoma; postural hypotension; head trauma or cerebral hemorrhage; pregnancy
WARNINGS / PRECAUTIONS
Disease-related concerns: Cardiovascular disease: Use with caution in patients with coronary artery disease and patients with hypotension. Increased intracranial pressure: Use with caution in patients with increased intracranial pressure.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
LACTATION — Excretion in breast milk unknown/not recommended
MONITORING PARAMETERS — Monitor blood pressure during therapy
INTERNATIONAL BRAND NAMES — Amyl Nitrite (NZ)
MECHANISM OF ACTION — Relaxes vascular smooth muscle; decreased venous ratios and arterial blood pressure; reduces left ventricular work; decreases myocardial O2 consumption; in cyanide poisoning, amyl nitrite converts hemoglobin to methemoglobin that binds with cyanide to form cyanate hemoglobin
PHARMACODYNAMICS / KINETICS
Onset of action: Angina: Within 30 seconds
Duration: 3-15 minutes
PATIENT INFORMATION — Lie down during administration. Crush ampul between fingers and then inhale through nostrils. May cause dizziness. Call paramedics or have someone take you to the hospital immediately if pain is not relieved after 3 doses.
Amsacrine
PHARMACOLOGIC CATEGORY
Antineoplastic Agent
DOSING: ADULTS — Details concerning dosing in combination regimens should also be consulted.
Acute leukemia: I.V.:
Induction: 75-125 mg/m2/day for 5 days every 3-4 weeks (125 mg/m2/day is preferred; two courses may be necessary to achieve induction; increase dose by 20% in second and subsequent cycles if marrow hypoplasia not achieved and in absence of significant toxicity in previous course.)
Maintenance: Once remission has been achieved, maintenance dose should be ~50% of induction dose, administered every 4-8 weeks, depending on blood counts and marrow recovery
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983:
Serum creatinine 1.2-1.8 mg/dL: No adjustment recommended
Serum creatinine 2-3 mg/dL, oliguric patients: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: BUN >20 mg/dL or serum creatinine >1.5 mg/dL: Administer 75% of dose
DOSING: HEPATIC IMPAIRMENT — Bilirubin >2 mg/dL: Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983: Bilirubin >2 mg/dL: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: Bilirubin >2 mg/dL: Administer 75% of dose
Koren, 1992: Severe hepatic dysfunction: Administer ≤ 50% of dose
DOSING: ADJUSTMENT FOR TOXICITY — Consider decreasing dose by 20% if life-threatening infection or hemorrhage occurred in previous cycle; delay second and subsequent cycles until recovery from myelosuppression or evidence of leukemic infiltrate is evident.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [supplied with L-lactic acid 0.0353 M 13.5 mL] [not available in the U.S.]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [not available in the U.S.]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse over 60-90 minutes; avoid extravasation.
COMPATIBILITY — Stable in D5W; incompatible with BNS, D5NS, D51/4NS, D51/2NS, D5LR, D10NS, NSS, LR, chloride ion. Amsacrine forms an immediate precipitate in the presence of chloride ion; do not mix with drugs that are chloride or hydrochloride salts.
Y-site administration: Compatible: Amikacin, chlorpromazine, clindamycin, cytarabine, dexamethasone, diphenhydramine, famotidine, fludarabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, lorazepam, morphine, prochlorperazine, promethazine, ranitidine, sodium bicarbonate, tobramycin, vancomycin. Incompatible: Acyclovir, amphotericin, aztreonam, calcium chloride, ceftazidime, ceftriaxone, cephalothin, cimetidine, cisplatin, filgrastim, furosemide, ganciclovir, heparin, methylprednisolone, metoclopramide, ondansetron, potassium chloride, sargramostim.
Compatibility when admixed: Compatible: Sodium bicarbonate, bleomycin
USE — Canada: Refractory acute leukemia
USE - UNLABELED / INVESTIGATIONAL — Acute myeloid leukemia (AML)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Gastrointestinal: Nausea (>10%), vomiting (>10%), stomatitis (>10%), diarrhea (>10%), perirectal abscess (>10%), abdominal pain (>10%)
Hematologic: Myelosuppression, leukopenia (nadir: 11-13 days; recovery: days 17-25)
Frequency not defined:
Cardiovascular: Atrial tachyarrhythmia, atrial tachycardia, atrial fibrillation, bradycardia, cardiomyopathy (rare), cardiopulmonary arrest, CHF (rare); ECG changes (QT prolongation, nonspecific ST segment or T wave changes); ejection fraction decreased, hypotension, sinus tachycardia, tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachyarrhythmia
Central nervous system: Confusion, dizziness, emotional lability, fever, headache, hypoesthesia, lethargy, seizure
Dermatologic: Alopecia, cutaneous inflammatory reaction, dermatologic reaction, purpura, rash (purpuric or maculopapular), urticaria
Gastrointestinal: Anorexia, dysphagia, gingivitis, gum hemorrhage, hematemesis, weight changes
Genitourinary: Orange-red discoloration of the urine
Hematologic: Anemia, granulocytopenia, hemorrhage, pancytopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, AST increased, bilirubin increased, hepatic insufficiency, hepatitis, hepatotoxicity, jaundice, progressive liver failure
Local: Injection site inflammation, phlebitis
Neuromuscular & skeletal: Musculoskeletal pain, paresthesia, weakness
Renal: BUN increased, creatinine increased, hematuria, proteinuria, renal failure
Respiratory: Dyspnea
Miscellaneous: Allergic reaction, infection
CONTRAINDICATIONS — Hypersensitivity to amsacrine, acridine derivatives, or any component of the formulation; pre-existing bone marrow suppression due to chemotherapy or radiation therapy
WARNINGS / PRECAUTIONS
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects: Bone marrow suppression: Myelosuppression, including transient leukopenia, is a common toxicity; prolonged marrow aplasia may occur. May require dose reduction, therapy interruption or treatment delay. Cardiovascular effects: Acute cardiotoxicity, including arrhythmia, ECG changes, and rarely, cardiomyopathy and CHF, have been reported with use, although generally not considered to be a cumulative dose effect. Risk factors for cardiotoxicity may include hypokalemia and a history of anthracycline therapy. Correct fluid and electrolyte imbalance prior to treatment initiation. Use with caution in patients with underlying cardiovascular disease. Tumor lysis syndrome: Tumor lysis syndrome may occur; adequate hydration and prophylactic uric acid reduction should be considered prior to or during treatment; monitor closely.
Disease-related concerns: Hepatic impairment: Use with caution in patients with significant hepatic impairment (bilirubin >2 mg/dL); toxicity may be increased. Hepatic metabolism and biliary excretion are major routes of elimination. Dosage reductions may be recommended. Evaluate hepatic function prior to and during treatment. Hypokalemia: Serum potassium should be >4 mEq/L prior to administration (Arlin, 1988). The risk for arrhythmia is decreased by ensuring normal potassium levels. Renal impairment: Use with caution in patients with significant renal impairment (BUN >20 mg/dL; serum creatinine >1.2 mg/dL); toxicity may be increased. Dosage reductions may be recommended. Evaluate renal function prior to and during treatment.
Concurrent drug therapy issues: Anthracyclines: Use with caution in patients who have received high cumulative doses of anthracyclines (may increase the risk for cardiotoxicity). Vaccinations: Avoid vaccination with live virus vaccines during treatment.
RESTRICTIONS — Not available in U.S.
DRUG INTERACTIONS
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
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
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. 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
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — Breast-feeding should be discontinued prior to treatment.
MONITORING PARAMETERS
CBC with differential, bone marrow studies, serum potassium, hepatic function, renal function; ECG (during and after infusion)
CANADIAN BRAND NAMES — AMSA PD
INTERNATIONAL BRAND NAMES — Amekrin (DK, SE); Amsidine (BE, NL); Amsidyl (AU)
MECHANISM OF ACTION — Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA; inhibits topoisomerase II activity.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 1.67 L/kg; minimal CNS penetration
Protein binding: 96% to 98%
Metabolism: Hepatic, to inactive metabolites (major metabolite is 5' glutathione conjugate)
Half-life elimination: 1.4-5 hours; Terminal: 8-9 hours
Excretion: Bile; urine (35%; 20% as unchanged drug)
PATIENT INFORMATION — This drug may cause darkening or discoloration of the urine for 24-48 hours. Watch for fever, malaise, bleeding, bruising, sore throat or mouth, difficulty swallowing, or for pain, redness, or swelling at the injection site.
Antineoplastic Agent
DOSING: ADULTS — Details concerning dosing in combination regimens should also be consulted.
Acute leukemia: I.V.:
Induction: 75-125 mg/m2/day for 5 days every 3-4 weeks (125 mg/m2/day is preferred; two courses may be necessary to achieve induction; increase dose by 20% in second and subsequent cycles if marrow hypoplasia not achieved and in absence of significant toxicity in previous course.)
Maintenance: Once remission has been achieved, maintenance dose should be ~50% of induction dose, administered every 4-8 weeks, depending on blood counts and marrow recovery
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983:
Serum creatinine 1.2-1.8 mg/dL: No adjustment recommended
Serum creatinine 2-3 mg/dL, oliguric patients: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: BUN >20 mg/dL or serum creatinine >1.5 mg/dL: Administer 75% of dose
DOSING: HEPATIC IMPAIRMENT — Bilirubin >2 mg/dL: Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983: Bilirubin >2 mg/dL: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: Bilirubin >2 mg/dL: Administer 75% of dose
Koren, 1992: Severe hepatic dysfunction: Administer ≤ 50% of dose
DOSING: ADJUSTMENT FOR TOXICITY — Consider decreasing dose by 20% if life-threatening infection or hemorrhage occurred in previous cycle; delay second and subsequent cycles until recovery from myelosuppression or evidence of leukemic infiltrate is evident.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [supplied with L-lactic acid 0.0353 M 13.5 mL] [not available in the U.S.]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [not available in the U.S.]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse over 60-90 minutes; avoid extravasation.
COMPATIBILITY — Stable in D5W; incompatible with BNS, D5NS, D51/4NS, D51/2NS, D5LR, D10NS, NSS, LR, chloride ion. Amsacrine forms an immediate precipitate in the presence of chloride ion; do not mix with drugs that are chloride or hydrochloride salts.
Y-site administration: Compatible: Amikacin, chlorpromazine, clindamycin, cytarabine, dexamethasone, diphenhydramine, famotidine, fludarabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, lorazepam, morphine, prochlorperazine, promethazine, ranitidine, sodium bicarbonate, tobramycin, vancomycin. Incompatible: Acyclovir, amphotericin, aztreonam, calcium chloride, ceftazidime, ceftriaxone, cephalothin, cimetidine, cisplatin, filgrastim, furosemide, ganciclovir, heparin, methylprednisolone, metoclopramide, ondansetron, potassium chloride, sargramostim.
Compatibility when admixed: Compatible: Sodium bicarbonate, bleomycin
USE — Canada: Refractory acute leukemia
USE - UNLABELED / INVESTIGATIONAL — Acute myeloid leukemia (AML)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Gastrointestinal: Nausea (>10%), vomiting (>10%), stomatitis (>10%), diarrhea (>10%), perirectal abscess (>10%), abdominal pain (>10%)
Hematologic: Myelosuppression, leukopenia (nadir: 11-13 days; recovery: days 17-25)
Frequency not defined:
Cardiovascular: Atrial tachyarrhythmia, atrial tachycardia, atrial fibrillation, bradycardia, cardiomyopathy (rare), cardiopulmonary arrest, CHF (rare); ECG changes (QT prolongation, nonspecific ST segment or T wave changes); ejection fraction decreased, hypotension, sinus tachycardia, tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachyarrhythmia
Central nervous system: Confusion, dizziness, emotional lability, fever, headache, hypoesthesia, lethargy, seizure
Dermatologic: Alopecia, cutaneous inflammatory reaction, dermatologic reaction, purpura, rash (purpuric or maculopapular), urticaria
Gastrointestinal: Anorexia, dysphagia, gingivitis, gum hemorrhage, hematemesis, weight changes
Genitourinary: Orange-red discoloration of the urine
Hematologic: Anemia, granulocytopenia, hemorrhage, pancytopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, AST increased, bilirubin increased, hepatic insufficiency, hepatitis, hepatotoxicity, jaundice, progressive liver failure
Local: Injection site inflammation, phlebitis
Neuromuscular & skeletal: Musculoskeletal pain, paresthesia, weakness
Renal: BUN increased, creatinine increased, hematuria, proteinuria, renal failure
Respiratory: Dyspnea
Miscellaneous: Allergic reaction, infection
CONTRAINDICATIONS — Hypersensitivity to amsacrine, acridine derivatives, or any component of the formulation; pre-existing bone marrow suppression due to chemotherapy or radiation therapy
WARNINGS / PRECAUTIONS
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects: Bone marrow suppression: Myelosuppression, including transient leukopenia, is a common toxicity; prolonged marrow aplasia may occur. May require dose reduction, therapy interruption or treatment delay. Cardiovascular effects: Acute cardiotoxicity, including arrhythmia, ECG changes, and rarely, cardiomyopathy and CHF, have been reported with use, although generally not considered to be a cumulative dose effect. Risk factors for cardiotoxicity may include hypokalemia and a history of anthracycline therapy. Correct fluid and electrolyte imbalance prior to treatment initiation. Use with caution in patients with underlying cardiovascular disease. Tumor lysis syndrome: Tumor lysis syndrome may occur; adequate hydration and prophylactic uric acid reduction should be considered prior to or during treatment; monitor closely.
Disease-related concerns: Hepatic impairment: Use with caution in patients with significant hepatic impairment (bilirubin >2 mg/dL); toxicity may be increased. Hepatic metabolism and biliary excretion are major routes of elimination. Dosage reductions may be recommended. Evaluate hepatic function prior to and during treatment. Hypokalemia: Serum potassium should be >4 mEq/L prior to administration (Arlin, 1988). The risk for arrhythmia is decreased by ensuring normal potassium levels. Renal impairment: Use with caution in patients with significant renal impairment (BUN >20 mg/dL; serum creatinine >1.2 mg/dL); toxicity may be increased. Dosage reductions may be recommended. Evaluate renal function prior to and during treatment.
Concurrent drug therapy issues: Anthracyclines: Use with caution in patients who have received high cumulative doses of anthracyclines (may increase the risk for cardiotoxicity). Vaccinations: Avoid vaccination with live virus vaccines during treatment.
RESTRICTIONS — Not available in U.S.
DRUG INTERACTIONS
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
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
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. 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
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — Breast-feeding should be discontinued prior to treatment.
MONITORING PARAMETERS
CBC with differential, bone marrow studies, serum potassium, hepatic function, renal function; ECG (during and after infusion)
CANADIAN BRAND NAMES — AMSA PD
INTERNATIONAL BRAND NAMES — Amekrin (DK, SE); Amsidine (BE, NL); Amsidyl (AU)
MECHANISM OF ACTION — Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA; inhibits topoisomerase II activity.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 1.67 L/kg; minimal CNS penetration
Protein binding: 96% to 98%
Metabolism: Hepatic, to inactive metabolites (major metabolite is 5' glutathione conjugate)
Half-life elimination: 1.4-5 hours; Terminal: 8-9 hours
Excretion: Bile; urine (35%; 20% as unchanged drug)
PATIENT INFORMATION — This drug may cause darkening or discoloration of the urine for 24-48 hours. Watch for fever, malaise, bleeding, bruising, sore throat or mouth, difficulty swallowing, or for pain, redness, or swelling at the injection site.
Amsacrine
PHARMACOLOGIC CATEGORY
Antineoplastic Agent
DOSING: ADULTS — Details concerning dosing in combination regimens should also be consulted.
Acute leukemia: I.V.:
Induction: 75-125 mg/m2/day for 5 days every 3-4 weeks (125 mg/m2/day is preferred; two courses may be necessary to achieve induction; increase dose by 20% in second and subsequent cycles if marrow hypoplasia not achieved and in absence of significant toxicity in previous course.)
Maintenance: Once remission has been achieved, maintenance dose should be ~50% of induction dose, administered every 4-8 weeks, depending on blood counts and marrow recovery
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983:
Serum creatinine 1.2-1.8 mg/dL: No adjustment recommended
Serum creatinine 2-3 mg/dL, oliguric patients: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: BUN >20 mg/dL or serum creatinine >1.5 mg/dL: Administer 75% of dose
DOSING: HEPATIC IMPAIRMENT — Bilirubin >2 mg/dL: Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983: Bilirubin >2 mg/dL: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: Bilirubin >2 mg/dL: Administer 75% of dose
Koren, 1992: Severe hepatic dysfunction: Administer ≤ 50% of dose
DOSING: ADJUSTMENT FOR TOXICITY — Consider decreasing dose by 20% if life-threatening infection or hemorrhage occurred in previous cycle; delay second and subsequent cycles until recovery from myelosuppression or evidence of leukemic infiltrate is evident.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [supplied with L-lactic acid 0.0353 M 13.5 mL] [not available in the U.S.]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [not available in the U.S.]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse over 60-90 minutes; avoid extravasation.
COMPATIBILITY — Stable in D5W; incompatible with BNS, D5NS, D51/4NS, D51/2NS, D5LR, D10NS, NSS, LR, chloride ion. Amsacrine forms an immediate precipitate in the presence of chloride ion; do not mix with drugs that are chloride or hydrochloride salts.
Y-site administration: Compatible: Amikacin, chlorpromazine, clindamycin, cytarabine, dexamethasone, diphenhydramine, famotidine, fludarabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, lorazepam, morphine, prochlorperazine, promethazine, ranitidine, sodium bicarbonate, tobramycin, vancomycin. Incompatible: Acyclovir, amphotericin, aztreonam, calcium chloride, ceftazidime, ceftriaxone, cephalothin, cimetidine, cisplatin, filgrastim, furosemide, ganciclovir, heparin, methylprednisolone, metoclopramide, ondansetron, potassium chloride, sargramostim.
Compatibility when admixed: Compatible: Sodium bicarbonate, bleomycin
USE — Canada: Refractory acute leukemia
USE - UNLABELED / INVESTIGATIONAL — Acute myeloid leukemia (AML)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Gastrointestinal: Nausea (>10%), vomiting (>10%), stomatitis (>10%), diarrhea (>10%), perirectal abscess (>10%), abdominal pain (>10%)
Hematologic: Myelosuppression, leukopenia (nadir: 11-13 days; recovery: days 17-25)
Frequency not defined:
Cardiovascular: Atrial tachyarrhythmia, atrial tachycardia, atrial fibrillation, bradycardia, cardiomyopathy (rare), cardiopulmonary arrest, CHF (rare); ECG changes (QT prolongation, nonspecific ST segment or T wave changes); ejection fraction decreased, hypotension, sinus tachycardia, tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachyarrhythmia
Central nervous system: Confusion, dizziness, emotional lability, fever, headache, hypoesthesia, lethargy, seizure
Dermatologic: Alopecia, cutaneous inflammatory reaction, dermatologic reaction, purpura, rash (purpuric or maculopapular), urticaria
Gastrointestinal: Anorexia, dysphagia, gingivitis, gum hemorrhage, hematemesis, weight changes
Genitourinary: Orange-red discoloration of the urine
Hematologic: Anemia, granulocytopenia, hemorrhage, pancytopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, AST increased, bilirubin increased, hepatic insufficiency, hepatitis, hepatotoxicity, jaundice, progressive liver failure
Local: Injection site inflammation, phlebitis
Neuromuscular & skeletal: Musculoskeletal pain, paresthesia, weakness
Renal: BUN increased, creatinine increased, hematuria, proteinuria, renal failure
Respiratory: Dyspnea
Miscellaneous: Allergic reaction, infection
CONTRAINDICATIONS — Hypersensitivity to amsacrine, acridine derivatives, or any component of the formulation; pre-existing bone marrow suppression due to chemotherapy or radiation therapy
WARNINGS / PRECAUTIONS
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects: Bone marrow suppression: Myelosuppression, including transient leukopenia, is a common toxicity; prolonged marrow aplasia may occur. May require dose reduction, therapy interruption or treatment delay. Cardiovascular effects: Acute cardiotoxicity, including arrhythmia, ECG changes, and rarely, cardiomyopathy and CHF, have been reported with use, although generally not considered to be a cumulative dose effect. Risk factors for cardiotoxicity may include hypokalemia and a history of anthracycline therapy. Correct fluid and electrolyte imbalance prior to treatment initiation. Use with caution in patients with underlying cardiovascular disease. Tumor lysis syndrome: Tumor lysis syndrome may occur; adequate hydration and prophylactic uric acid reduction should be considered prior to or during treatment; monitor closely.
Disease-related concerns: Hepatic impairment: Use with caution in patients with significant hepatic impairment (bilirubin >2 mg/dL); toxicity may be increased. Hepatic metabolism and biliary excretion are major routes of elimination. Dosage reductions may be recommended. Evaluate hepatic function prior to and during treatment. Hypokalemia: Serum potassium should be >4 mEq/L prior to administration (Arlin, 1988). The risk for arrhythmia is decreased by ensuring normal potassium levels. Renal impairment: Use with caution in patients with significant renal impairment (BUN >20 mg/dL; serum creatinine >1.2 mg/dL); toxicity may be increased. Dosage reductions may be recommended. Evaluate renal function prior to and during treatment.
Concurrent drug therapy issues: Anthracyclines: Use with caution in patients who have received high cumulative doses of anthracyclines (may increase the risk for cardiotoxicity). Vaccinations: Avoid vaccination with live virus vaccines during treatment.
RESTRICTIONS — Not available in U.S.
DRUG INTERACTIONS
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
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
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. 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
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — Breast-feeding should be discontinued prior to treatment.
MONITORING PARAMETERS
CBC with differential, bone marrow studies, serum potassium, hepatic function, renal function; ECG (during and after infusion)
CANADIAN BRAND NAMES — AMSA PD
INTERNATIONAL BRAND NAMES — Amekrin (DK, SE); Amsidine (BE, NL); Amsidyl (AU)
MECHANISM OF ACTION — Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA; inhibits topoisomerase II activity.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 1.67 L/kg; minimal CNS penetration
Protein binding: 96% to 98%
Metabolism: Hepatic, to inactive metabolites (major metabolite is 5' glutathione conjugate)
Half-life elimination: 1.4-5 hours; Terminal: 8-9 hours
Excretion: Bile; urine (35%; 20% as unchanged drug)
PATIENT INFORMATION — This drug may cause darkening or discoloration of the urine for 24-48 hours. Watch for fever, malaise, bleeding, bruising, sore throat or mouth, difficulty swallowing, or for pain, redness, or swelling at the injection site.
Antineoplastic Agent
DOSING: ADULTS — Details concerning dosing in combination regimens should also be consulted.
Acute leukemia: I.V.:
Induction: 75-125 mg/m2/day for 5 days every 3-4 weeks (125 mg/m2/day is preferred; two courses may be necessary to achieve induction; increase dose by 20% in second and subsequent cycles if marrow hypoplasia not achieved and in absence of significant toxicity in previous course.)
Maintenance: Once remission has been achieved, maintenance dose should be ~50% of induction dose, administered every 4-8 weeks, depending on blood counts and marrow recovery
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983:
Serum creatinine 1.2-1.8 mg/dL: No adjustment recommended
Serum creatinine 2-3 mg/dL, oliguric patients: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: BUN >20 mg/dL or serum creatinine >1.5 mg/dL: Administer 75% of dose
DOSING: HEPATIC IMPAIRMENT — Bilirubin >2 mg/dL: Dosage reduction recommended; specific guidelines from the manufacturer are not available; the following guidelines have been used by some clinicians:
Hall, 1983: Bilirubin >2 mg/dL: Administer 60% to 70% of dose; may increase subsequent dose based on toxicity.
Hornedo, 1985: Bilirubin >2 mg/dL: Administer 75% of dose
Koren, 1992: Severe hepatic dysfunction: Administer ≤ 50% of dose
DOSING: ADJUSTMENT FOR TOXICITY — Consider decreasing dose by 20% if life-threatening infection or hemorrhage occurred in previous cycle; delay second and subsequent cycles until recovery from myelosuppression or evidence of leukemic infiltrate is evident.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [supplied with L-lactic acid 0.0353 M 13.5 mL] [not available in the U.S.]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
AMSA PD [CAN]: 50 mg/mL (1.5 mL) [not available in the U.S.]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse over 60-90 minutes; avoid extravasation.
COMPATIBILITY — Stable in D5W; incompatible with BNS, D5NS, D51/4NS, D51/2NS, D5LR, D10NS, NSS, LR, chloride ion. Amsacrine forms an immediate precipitate in the presence of chloride ion; do not mix with drugs that are chloride or hydrochloride salts.
Y-site administration: Compatible: Amikacin, chlorpromazine, clindamycin, cytarabine, dexamethasone, diphenhydramine, famotidine, fludarabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, lorazepam, morphine, prochlorperazine, promethazine, ranitidine, sodium bicarbonate, tobramycin, vancomycin. Incompatible: Acyclovir, amphotericin, aztreonam, calcium chloride, ceftazidime, ceftriaxone, cephalothin, cimetidine, cisplatin, filgrastim, furosemide, ganciclovir, heparin, methylprednisolone, metoclopramide, ondansetron, potassium chloride, sargramostim.
Compatibility when admixed: Compatible: Sodium bicarbonate, bleomycin
USE — Canada: Refractory acute leukemia
USE - UNLABELED / INVESTIGATIONAL — Acute myeloid leukemia (AML)
ADVERSE REACTIONS SIGNIFICANT
>10%:
Gastrointestinal: Nausea (>10%), vomiting (>10%), stomatitis (>10%), diarrhea (>10%), perirectal abscess (>10%), abdominal pain (>10%)
Hematologic: Myelosuppression, leukopenia (nadir: 11-13 days; recovery: days 17-25)
Frequency not defined:
Cardiovascular: Atrial tachyarrhythmia, atrial tachycardia, atrial fibrillation, bradycardia, cardiomyopathy (rare), cardiopulmonary arrest, CHF (rare); ECG changes (QT prolongation, nonspecific ST segment or T wave changes); ejection fraction decreased, hypotension, sinus tachycardia, tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachyarrhythmia
Central nervous system: Confusion, dizziness, emotional lability, fever, headache, hypoesthesia, lethargy, seizure
Dermatologic: Alopecia, cutaneous inflammatory reaction, dermatologic reaction, purpura, rash (purpuric or maculopapular), urticaria
Gastrointestinal: Anorexia, dysphagia, gingivitis, gum hemorrhage, hematemesis, weight changes
Genitourinary: Orange-red discoloration of the urine
Hematologic: Anemia, granulocytopenia, hemorrhage, pancytopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased, AST increased, bilirubin increased, hepatic insufficiency, hepatitis, hepatotoxicity, jaundice, progressive liver failure
Local: Injection site inflammation, phlebitis
Neuromuscular & skeletal: Musculoskeletal pain, paresthesia, weakness
Renal: BUN increased, creatinine increased, hematuria, proteinuria, renal failure
Respiratory: Dyspnea
Miscellaneous: Allergic reaction, infection
CONTRAINDICATIONS — Hypersensitivity to amsacrine, acridine derivatives, or any component of the formulation; pre-existing bone marrow suppression due to chemotherapy or radiation therapy
WARNINGS / PRECAUTIONS
Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects: Bone marrow suppression: Myelosuppression, including transient leukopenia, is a common toxicity; prolonged marrow aplasia may occur. May require dose reduction, therapy interruption or treatment delay. Cardiovascular effects: Acute cardiotoxicity, including arrhythmia, ECG changes, and rarely, cardiomyopathy and CHF, have been reported with use, although generally not considered to be a cumulative dose effect. Risk factors for cardiotoxicity may include hypokalemia and a history of anthracycline therapy. Correct fluid and electrolyte imbalance prior to treatment initiation. Use with caution in patients with underlying cardiovascular disease. Tumor lysis syndrome: Tumor lysis syndrome may occur; adequate hydration and prophylactic uric acid reduction should be considered prior to or during treatment; monitor closely.
Disease-related concerns: Hepatic impairment: Use with caution in patients with significant hepatic impairment (bilirubin >2 mg/dL); toxicity may be increased. Hepatic metabolism and biliary excretion are major routes of elimination. Dosage reductions may be recommended. Evaluate hepatic function prior to and during treatment. Hypokalemia: Serum potassium should be >4 mEq/L prior to administration (Arlin, 1988). The risk for arrhythmia is decreased by ensuring normal potassium levels. Renal impairment: Use with caution in patients with significant renal impairment (BUN >20 mg/dL; serum creatinine >1.2 mg/dL); toxicity may be increased. Dosage reductions may be recommended. Evaluate renal function prior to and during treatment.
Concurrent drug therapy issues: Anthracyclines: Use with caution in patients who have received high cumulative doses of anthracyclines (may increase the risk for cardiotoxicity). Vaccinations: Avoid vaccination with live virus vaccines during treatment.
RESTRICTIONS — Not available in U.S.
DRUG INTERACTIONS
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
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
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. 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
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
PREGNANCY IMPLICATIONS — Animal reproduction studies have not been conducted. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — Breast-feeding should be discontinued prior to treatment.
MONITORING PARAMETERS
CBC with differential, bone marrow studies, serum potassium, hepatic function, renal function; ECG (during and after infusion)
CANADIAN BRAND NAMES — AMSA PD
INTERNATIONAL BRAND NAMES — Amekrin (DK, SE); Amsidine (BE, NL); Amsidyl (AU)
MECHANISM OF ACTION — Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA; inhibits topoisomerase II activity.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 1.67 L/kg; minimal CNS penetration
Protein binding: 96% to 98%
Metabolism: Hepatic, to inactive metabolites (major metabolite is 5' glutathione conjugate)
Half-life elimination: 1.4-5 hours; Terminal: 8-9 hours
Excretion: Bile; urine (35%; 20% as unchanged drug)
PATIENT INFORMATION — This drug may cause darkening or discoloration of the urine for 24-48 hours. Watch for fever, malaise, bleeding, bruising, sore throat or mouth, difficulty swallowing, or for pain, redness, or swelling at the injection site.
Ampicillin and sulbactam
U.S. BRAND NAMES — Unasyn®
PHARMACOLOGIC CATEGORY
Antibiotic, Penicillin
DOSING: ADULTS — Doses expressed as ampicillin/sulbactam combination.
Susceptible infections: I.M., I.V.: 1.5-3 g every 6 hours (maximum: Unasyn® 12 g)
Amnionitis, cholangitis, diverticulitis, endometritis, endophthalmitis, epididymitis/orchitis, liver abscess, osteomyelitis (diabetic foot), peritonitis: I.V.: 3 g every 6 hours
Endocarditis: I.V.: 3 g every 6 hours with gentamicin or vancomycin for 4-6 weeks
Orbital cellulitis: I.V.: 1.5 g every 6 hours
Parapharyngeal space infections: I.V.: 3 g every 6 hours
Pasteurella multocida(human, canine/feline bites): I.V.: 1.5-3 g every 6 hours
Pelvic inflammatory disease: I.V.: 3 g every 6 hours with doxycycline
Peritonitis (CAPD): Intraperitoneal:
Anuric, intermittent: 3 g every 12 hours
Anuric, continuous: Loading dose: 1.5 g; maintenance dose: 150 mg
Pneumonia:
Aspiration, community-acquired: I.V.: 1.5-3 g every 6 hours
Hospital-acquired: I.V.: 3 g every 6 hours
Urinary tract infections, pyelonephritis: I.V.: 3 g every 6 hours for 14 days
DOSING: PEDIATRIC
(For additional information see "Ampicillin and sulbactam: Pediatric drug information")
Susceptible infections: Children ≥ 1 year: I.V.: 100-400 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®). Note: The American Academy of Pediatrics recommends a dose of up to 300 mg/kg/day for severe infection in infants >1 month of age.
Epiglottitis: Children ≥ 1 year: I.V.: 100-200 mg ampicillin/kg/day divided in 4 doses
Mild-to-moderate infections: Children ≥ 1 year: I.V.: 100-200 mg ampicillin/kg/day (150-300 mg Unasyn®) divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®)
Peritonsillar and retropharyngeal abscess: Children ≥ 1 year: I.V.: 50 mg ampicillin/kg/dose every 6 hours
Severe infections: Children ≥ 1 year: I.V.: 200-400 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Clcr 15-29 mL/minute: Administer every 12 hours
Clcr 5-14 mL/minute: Administer every 24 hours
Hemodialysis: Give dose after hemodialysis
Continuous ambulatory peritoneal dialysis (CAPD): 3 g every 24 hours
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH: 3 g every 12 hours
CVVHD/CVVHDF: 3 g every 8 hours
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g [contains sodium 115 mg (5 mEq)/1.5 g)]; 3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium 115 mg (5 mEq)/1.5 g)]; 15 g: Ampicillin 10 g and sulbactam 5 g [bulk package; contains sodium 115 mg (5 mEq)/1.5 g]
Unasyn®:
1.5 g: Ampicillin 1 g and sulbactam 0.5 g [contains sodium 115 mg (5 mEq)/1.5 g)]
3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium 115 mg (5 mEq)/1.5 g)]
15 g: Ampicillin 10 g and sulbactam 5 g [bulk package; contains sodium 115 mg (5 mEq)/1.5 g)]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution: 1.5 g [ampicillin 1 g and sulbactam 0.5 g]; 3 g [ampicillin 2 g and sulbactam 1 g]; 15 g [ampicillin 10 g and sulbactam 5 g]
Unasyn®: 1.5 g [ampicillin 1 g and sulbactam 0.5 g]; 3 g [ampicillin 2 g and sulbactam 1 g]; 15 g [ampicillin 10 g and sulbactam 5 g]; 15 g [ampicillin 10 g and sulbactam 5 g
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer around-the-clock to promote less variation in peak and trough serum levels. Administer by slow injection over 10-15 minutes or I.V. over 15-30 minutes. Ampicillin and gentamicin should not be mixed in the same I.V. tubing.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
COMPATIBILITY — Stable in NS; variable stability (consult detailed reference) in D51/2NS, D5W, LR.
Y-site administration: Compatible: Amifostine, aztreonam, cefepime, docetaxel, enalaprilat, etoposide, famotidine, filgrastim, fluconazole, fludarabine, gatifloxacin, gemcitabine, granisetron, heparin, insulin (regular), linezolid, meperidine, morphine, paclitaxel, remifentanil, tacrolimus, teniposide, theophylline, thiotepa. Incompatible: Aminoglycosides (gentamicin, tobramycin), amphotericin B cholesteryl sulfate complex, ciprofloxacin, idarubicin, ondansetron, sargramostim. Variable (consult detailed reference): Cisatracurium, diltiazem, vancomycin.
Compatibility when admixed: Compatible: Aztreonam. Incompatible: Aminoglycosides.
USE — Treatment of susceptible bacterial infections involved with skin and skin structure, intra-abdominal infections, gynecological infections; spectrum is that of ampicillin plus organisms producing beta-lactamases such as S. aureus, H. influenzae, E. coli, Klebsiella, Acinetobacter, Enterobacter, and anaerobes
ADVERSE REACTIONS SIGNIFICANT — Also see Ampicillin.
>10%: Local: Pain at injection site (I.M.)
1% to 10%:
Dermatologic: Rash
Gastrointestinal: Diarrhea
Local: Pain at injection site (I.V.), thrombophlebitis
Miscellaneous: Allergic reaction (may include serum sickness, urticaria, bronchospasm, hypotension, etc)
<1% (Limited to important or life-threatening): Abdominal distension, candidiasis, chest pain, chills, dysuria, edema, epistaxis, erythema, facial swelling, fatigue, flatulence, glossitis, hairy tongue, headache, interstitial nephritis, itching, liver enzymes increased, malaise, mucosal bleeding, nausea, pseudomembranous colitis, seizure, substernal pain, throat tightness, thrombocytopenia, urine retention, vomiting
CONTRAINDICATIONS — Hypersensitivity to ampicillin, sulbactam, penicillins, or any component of the formulations
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients. Rash: Appearance of a rash should be carefully evaluated to differentiate a nonallergic ampicillin rash from a hypersensitivity reaction; rash occurs in 5% to 10% of children and is a generalized dull red, maculopapular rash, generally appearing 3-14 days after the start of therapy. It normally begins on the trunk and spreads over most of the body. It may be most intense at pressure areas, elbows, and knees. Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns: Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash during therapy; ampicillin-class antibiotics not recommended in these patients. Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Special populations: Pediatrics: Safety and efficacy have not been established in children <1 year of age.
DRUG INTERACTIONS
Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Risk C: Monitor therapy
Atenolol: Ampicillin may decrease the bioavailability of Atenolol. Risk C: Monitor therapy
Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Risk D: Consider therapy modification
Uricosuric Agents: May decrease the excretion of Penicillins. Risk C: Monitor therapy
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Adverse events have not been observed in animal studies; therefore, ampicillin/sulbactam is classified as pregnancy category B. Both ampicillin and sulbactam cross the placenta. When used during pregnancy, pharmacokinetic changes have been observed with ampicillin alone (refer to the Ampicillin monograph for details).
LACTATION — Enters breast milk/use caution
BREAST-FEEDING CONSIDERATIONS — Ampicillin and sulbactam are both excreted into breast milk in low concentrations. The manufacturer recommends that caution be used if administering to lactating women. Nondose-related effects could include modification of bowel flora and allergic sensitization of the infant. The maternal dose of sulbactam does not need altered in the postpartum period. Also refer to the Ampicillin monograph.
DIETARY CONSIDERATIONS — Sodium content of 1.5 g injection: 115 mg (5 mEq)
MONITORING PARAMETERS — With prolonged therapy, monitor hematologic, renal, and hepatic function; monitor for signs of anaphylaxis during first dose
CANADIAN BRAND NAMES — Unasyn®
INTERNATIONAL BRAND NAMES — Ampibactan (VE); Amplisul (EC); Ansulina (TW); Baccillin (KP); Bactacin (KP); Bactesyn (ID); Easyn (MY); Picyn (ID); Prixin (PY); Rukasyn (KP); Sulbaccin (TH); Sulbacin (IN, KP, MY, PH); Sultamicilina (AR); Ubacillin (KP); Ubactam (KP); Unacid (DE); Unacim (FR); Unasyn (AE, AT, BF, BH, BJ, BR, CI, CL, CN, CO, CR, CY, CZ, EC, EE, EG, ET, GH, GM, GN, GT, HK, HN, ID, IL, IQ, IR, IT, JO, KE, KP, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, NI, OM, PA, PE, PH, QA, SA, SC, SD, SL, SN, SV, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Unasyna (AR, UY)
MECHANISM OF ACTION — The addition of sulbactam, a beta-lactamase inhibitor, to ampicillin extends the spectrum of ampicillin to include some beta-lactamase-producing organisms; inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
PHARMACODYNAMICS / KINETICS
Ampicillin: See Ampicillin.
Sulbactam:
Distribution: Bile, blister, and tissue fluids
Protein binding: 38%
Half-life elimination: Normal renal function: 1-1.3 hours
Excretion: Urine (~75% to 85% as unchanged drug) within 8 hours
PHARMACOLOGIC CATEGORY
Antibiotic, Penicillin
DOSING: ADULTS — Doses expressed as ampicillin/sulbactam combination.
Susceptible infections: I.M., I.V.: 1.5-3 g every 6 hours (maximum: Unasyn® 12 g)
Amnionitis, cholangitis, diverticulitis, endometritis, endophthalmitis, epididymitis/orchitis, liver abscess, osteomyelitis (diabetic foot), peritonitis: I.V.: 3 g every 6 hours
Endocarditis: I.V.: 3 g every 6 hours with gentamicin or vancomycin for 4-6 weeks
Orbital cellulitis: I.V.: 1.5 g every 6 hours
Parapharyngeal space infections: I.V.: 3 g every 6 hours
Pasteurella multocida(human, canine/feline bites): I.V.: 1.5-3 g every 6 hours
Pelvic inflammatory disease: I.V.: 3 g every 6 hours with doxycycline
Peritonitis (CAPD): Intraperitoneal:
Anuric, intermittent: 3 g every 12 hours
Anuric, continuous: Loading dose: 1.5 g; maintenance dose: 150 mg
Pneumonia:
Aspiration, community-acquired: I.V.: 1.5-3 g every 6 hours
Hospital-acquired: I.V.: 3 g every 6 hours
Urinary tract infections, pyelonephritis: I.V.: 3 g every 6 hours for 14 days
DOSING: PEDIATRIC
(For additional information see "Ampicillin and sulbactam: Pediatric drug information")
Susceptible infections: Children ≥ 1 year: I.V.: 100-400 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®). Note: The American Academy of Pediatrics recommends a dose of up to 300 mg/kg/day for severe infection in infants >1 month of age.
Epiglottitis: Children ≥ 1 year: I.V.: 100-200 mg ampicillin/kg/day divided in 4 doses
Mild-to-moderate infections: Children ≥ 1 year: I.V.: 100-200 mg ampicillin/kg/day (150-300 mg Unasyn®) divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®)
Peritonsillar and retropharyngeal abscess: Children ≥ 1 year: I.V.: 50 mg ampicillin/kg/dose every 6 hours
Severe infections: Children ≥ 1 year: I.V.: 200-400 mg ampicillin/kg/day divided every 6 hours (maximum: 8 g ampicillin/day, 12 g Unasyn®)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Clcr 15-29 mL/minute: Administer every 12 hours
Clcr 5-14 mL/minute: Administer every 24 hours
Hemodialysis: Give dose after hemodialysis
Continuous ambulatory peritoneal dialysis (CAPD): 3 g every 24 hours
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH: 3 g every 12 hours
CVVHD/CVVHDF: 3 g every 8 hours
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g [contains sodium 115 mg (5 mEq)/1.5 g)]; 3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium 115 mg (5 mEq)/1.5 g)]; 15 g: Ampicillin 10 g and sulbactam 5 g [bulk package; contains sodium 115 mg (5 mEq)/1.5 g]
Unasyn®:
1.5 g: Ampicillin 1 g and sulbactam 0.5 g [contains sodium 115 mg (5 mEq)/1.5 g)]
3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium 115 mg (5 mEq)/1.5 g)]
15 g: Ampicillin 10 g and sulbactam 5 g [bulk package; contains sodium 115 mg (5 mEq)/1.5 g)]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution: 1.5 g [ampicillin 1 g and sulbactam 0.5 g]; 3 g [ampicillin 2 g and sulbactam 1 g]; 15 g [ampicillin 10 g and sulbactam 5 g]
Unasyn®: 1.5 g [ampicillin 1 g and sulbactam 0.5 g]; 3 g [ampicillin 2 g and sulbactam 1 g]; 15 g [ampicillin 10 g and sulbactam 5 g]; 15 g [ampicillin 10 g and sulbactam 5 g
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — Administer around-the-clock to promote less variation in peak and trough serum levels. Administer by slow injection over 10-15 minutes or I.V. over 15-30 minutes. Ampicillin and gentamicin should not be mixed in the same I.V. tubing.
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.
COMPATIBILITY — Stable in NS; variable stability (consult detailed reference) in D51/2NS, D5W, LR.
Y-site administration: Compatible: Amifostine, aztreonam, cefepime, docetaxel, enalaprilat, etoposide, famotidine, filgrastim, fluconazole, fludarabine, gatifloxacin, gemcitabine, granisetron, heparin, insulin (regular), linezolid, meperidine, morphine, paclitaxel, remifentanil, tacrolimus, teniposide, theophylline, thiotepa. Incompatible: Aminoglycosides (gentamicin, tobramycin), amphotericin B cholesteryl sulfate complex, ciprofloxacin, idarubicin, ondansetron, sargramostim. Variable (consult detailed reference): Cisatracurium, diltiazem, vancomycin.
Compatibility when admixed: Compatible: Aztreonam. Incompatible: Aminoglycosides.
USE — Treatment of susceptible bacterial infections involved with skin and skin structure, intra-abdominal infections, gynecological infections; spectrum is that of ampicillin plus organisms producing beta-lactamases such as S. aureus, H. influenzae, E. coli, Klebsiella, Acinetobacter, Enterobacter, and anaerobes
ADVERSE REACTIONS SIGNIFICANT — Also see Ampicillin.
>10%: Local: Pain at injection site (I.M.)
1% to 10%:
Dermatologic: Rash
Gastrointestinal: Diarrhea
Local: Pain at injection site (I.V.), thrombophlebitis
Miscellaneous: Allergic reaction (may include serum sickness, urticaria, bronchospasm, hypotension, etc)
<1% (Limited to important or life-threatening): Abdominal distension, candidiasis, chest pain, chills, dysuria, edema, epistaxis, erythema, facial swelling, fatigue, flatulence, glossitis, hairy tongue, headache, interstitial nephritis, itching, liver enzymes increased, malaise, mucosal bleeding, nausea, pseudomembranous colitis, seizure, substernal pain, throat tightness, thrombocytopenia, urine retention, vomiting
CONTRAINDICATIONS — Hypersensitivity to ampicillin, sulbactam, penicillins, or any component of the formulations
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients. Rash: Appearance of a rash should be carefully evaluated to differentiate a nonallergic ampicillin rash from a hypersensitivity reaction; rash occurs in 5% to 10% of children and is a generalized dull red, maculopapular rash, generally appearing 3-14 days after the start of therapy. It normally begins on the trunk and spreads over most of the body. It may be most intense at pressure areas, elbows, and knees. Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns: Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash during therapy; ampicillin-class antibiotics not recommended in these patients. Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Special populations: Pediatrics: Safety and efficacy have not been established in children <1 year of age.
DRUG INTERACTIONS
Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Ampicillin. Risk C: Monitor therapy
Atenolol: Ampicillin may decrease the bioavailability of Atenolol. Risk C: Monitor therapy
Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy
Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Risk D: Consider therapy modification
Uricosuric Agents: May decrease the excretion of Penicillins. Risk C: Monitor therapy
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Adverse events have not been observed in animal studies; therefore, ampicillin/sulbactam is classified as pregnancy category B. Both ampicillin and sulbactam cross the placenta. When used during pregnancy, pharmacokinetic changes have been observed with ampicillin alone (refer to the Ampicillin monograph for details).
LACTATION — Enters breast milk/use caution
BREAST-FEEDING CONSIDERATIONS — Ampicillin and sulbactam are both excreted into breast milk in low concentrations. The manufacturer recommends that caution be used if administering to lactating women. Nondose-related effects could include modification of bowel flora and allergic sensitization of the infant. The maternal dose of sulbactam does not need altered in the postpartum period. Also refer to the Ampicillin monograph.
DIETARY CONSIDERATIONS — Sodium content of 1.5 g injection: 115 mg (5 mEq)
MONITORING PARAMETERS — With prolonged therapy, monitor hematologic, renal, and hepatic function; monitor for signs of anaphylaxis during first dose
CANADIAN BRAND NAMES — Unasyn®
INTERNATIONAL BRAND NAMES — Ampibactan (VE); Amplisul (EC); Ansulina (TW); Baccillin (KP); Bactacin (KP); Bactesyn (ID); Easyn (MY); Picyn (ID); Prixin (PY); Rukasyn (KP); Sulbaccin (TH); Sulbacin (IN, KP, MY, PH); Sultamicilina (AR); Ubacillin (KP); Ubactam (KP); Unacid (DE); Unacim (FR); Unasyn (AE, AT, BF, BH, BJ, BR, CI, CL, CN, CO, CR, CY, CZ, EC, EE, EG, ET, GH, GM, GN, GT, HK, HN, ID, IL, IQ, IR, IT, JO, KE, KP, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, NI, OM, PA, PE, PH, QA, SA, SC, SD, SL, SN, SV, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Unasyna (AR, UY)
MECHANISM OF ACTION — The addition of sulbactam, a beta-lactamase inhibitor, to ampicillin extends the spectrum of ampicillin to include some beta-lactamase-producing organisms; inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
PHARMACODYNAMICS / KINETICS
Ampicillin: See Ampicillin.
Sulbactam:
Distribution: Bile, blister, and tissue fluids
Protein binding: 38%
Half-life elimination: Normal renal function: 1-1.3 hours
Excretion: Urine (~75% to 85% as unchanged drug) within 8 hours
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