Monday, August 2, 2010

Abiu

A minor member of the Sapotaceae, the abiu, Pouteria caimito Radlk. (syns. Lucuma caimito Roem. & Schult.; Achras caimito Ruiz & Pavón), has acquired few vernacular names. In Colombia, it is called caimito, caimito amarilla, caimo or madura verde; in Ecuador, luma or cauje; in Venezuela, temare; in Brazil, abiu, abi, abio, abieiro or caimito. It is called yellow star apple in Trinidad.

Abiu
Plate LVII: ABIU, Pouteria caimito
Description

The tree has a pyramidal or rounded crown; is generally about 33 ft (10 m) high but may reach 115 ft (35 m) in favorable situations. A gummy latex, white or reddish, exudes from wounds in the bark. The leaves are alternate and highly variable; may be ovate-oblong, obovate or elliptic; 4 to 8 in (10-20 cm) long, 1 1/4 to 2 3/8 in (3-6 cm) wide; short-pointed at the apex, sometimes long-tapering at the base; smooth or with a few scattered hairs. The flowers, borne singly or in groups of 2 to 5 in the leaf axils, are cylindrical, 4- to 5-lobed, white or greenish; 1/6 to 1/3 in (4-8 mm) long. The fruit, downy when young, is ovoid, elliptical or round; 1 1/2 to 4 in (4-10 cm) long, sometimes having a short nipple at the apex; with smooth, tough, pale-yellow skin when ripe and fragrant, white, mucilaginous, translucent, mild-flavored, sweet or insipid pulp containing 1 to 4 oblong seeds, brown, with a pale hilum on one side. Until fully ripe, the fruit is permeated with latex and is very gummy and astringent.

Abiu
Fig. 109: The pale-yellow abiu (Poutertai caimito) as sold in the native market of Buenaventura, Colombia. The fruit is gummy with latex until it becomes fully ripe.

Origin and Distribution

The abiu is a denizen of the headwaters of the Amazon. It grows wild on the lower eastern slopes of the Andes from southwestern Venezuela to Peru. It is often cultivated around Iquitos, Peru. In Ecuador, it is common in the Province of Guayas and the fruits are sold in the markets of Guayaquil. It is much grown around Pará, Brazil; less frequently near Rio de Janeiro, and to a limited extent at Bahia. In Colombia, it is fairly common in the regions of Caquetá, Meta and Vaupés and it abounds in the adjacent areas of Amazonas, Venezuela. It has been growing for many years in Trinidad.

The plant explorers, Dorsett, Shamel and Popenoe, collected seeds for the United States Department of Agriculture in Bahia in 1914 (S.P.I. #37929). In 1915, seeds were received from Lavoras, Minas, Brazil (S.P.I. #41003). This species has been planted several times at the Agricultural Research and Education Center, Homestead, Florida, but most of the young plants have been killed by winter cold. A few trees planted in 1953 fruited in 1962.

Varieties

There is much variation in the form, size and quality of the fruits of seedling trees, some having firm flesh, some soft; and some are insipid, while others have agreeable flavor. At Puerto Ospina, along the Putamayo River in Colombia, there is a type that fruits in 4 years. The fruit is round and large. Near the River Inirida, in Vaupés, Colombia, there is a type that bears in one year from seed, but the fruits are small with little pulp.

Climate

The abiu is strictly tropical or near-tropical. It thrives best in a year-around warm and moist climate, yet Popenoe noted that it does well in somewhat cooler Rio de Janeiro. In Peru it has not been found above 2,000 ft (650 m), though in Colombia, it can be grown up to an elevation of 6,000 ft (1,900 m).

Soil

The tree is naturally suited to fertile, wet soil. It is subject to chlorosis in the limestone of southern Florida.

Season

The fruits are in season in March and April in Ecuador. They are sold in some Brazilian markets from September to April but only a few are seen in the much shorter season of February and March at Bahia. Fruits have matured in October in Florida. The abiu can be picked while underripe and firm for transport to markets.

Propagation and Culture

In Brazil, the washed seeds are dried in the shade and then planted, 3 together and 2 in (5 cm) deep in enriched soil. They will germinate in 15 to 20 days. When the seedlings are 4 in (10 cm) high, the 2 weakest are removed. The strong one is set out when 12 to 16 in (30-40 cm) high. Spacing is 17 x 20 ft (6 x 5 m). One year later, the lower branches are pruned. Fruiting will begin in 3 years; will be substantial in 5 years.

Pests and Diseases

Actually, the fruit has little value commercially because it is commonly damaged by small insects (bichos in Spanish and Portuguese). In Brazil, the chief pests are said to be fruit flies.

Food Uses

In Colombia, people who wish to eat the abiu. are advised to grease their lips beforehand to keep the gummy latex from clinging to them. It is mostly eaten out-of-hand but, in Pará, some types are used to make ices and ice cream.

Food Value Per 100 g of Edible Portion*
Calories 95
Moisture 74.1 g
Protein 2.1 g
Lipids 1.1 g
Glycerides 22.0 g
Fiber 3.0 g
Ash 0.7 g
Calcium 96.0 mg
Phosphorus 45.0 mg
Iron 1.8 mg
Vitamin B, 0.2 mg
Vitamin B2 0.2 mg
Niacin 3.4 mg
Ascorbic Acid 49.0 mg
Amino Acids (mg per g of nitrogen [N 6.25])
Lysine 316 mg
Methionine 178 mg
Threonine 219 mg
Tryptophan 57 mg

*According to analyses made in Brazil.

Other Uses

Wood: The wood is dense and heavy, hard, and valued for construction.

Medicinal Uses: In Brazil, the pulp, because of its mucilaginous nature, is eaten to relieve coughs, bronchitis and other pulmonary complaints. The latex is given as a vermifuge and purge and is applied on abscesses.

Abiu

A minor member of the Sapotaceae, the abiu, Pouteria caimito Radlk. (syns. Lucuma caimito Roem. & Schult.; Achras caimito Ruiz & Pavón), has acquired few vernacular names. In Colombia, it is called caimito, caimito amarilla, caimo or madura verde; in Ecuador, luma or cauje; in Venezuela, temare; in Brazil, abiu, abi, abio, abieiro or caimito. It is called yellow star apple in Trinidad.

Abiu
Plate LVII: ABIU, Pouteria caimito
Description

The tree has a pyramidal or rounded crown; is generally about 33 ft (10 m) high but may reach 115 ft (35 m) in favorable situations. A gummy latex, white or reddish, exudes from wounds in the bark. The leaves are alternate and highly variable; may be ovate-oblong, obovate or elliptic; 4 to 8 in (10-20 cm) long, 1 1/4 to 2 3/8 in (3-6 cm) wide; short-pointed at the apex, sometimes long-tapering at the base; smooth or with a few scattered hairs. The flowers, borne singly or in groups of 2 to 5 in the leaf axils, are cylindrical, 4- to 5-lobed, white or greenish; 1/6 to 1/3 in (4-8 mm) long. The fruit, downy when young, is ovoid, elliptical or round; 1 1/2 to 4 in (4-10 cm) long, sometimes having a short nipple at the apex; with smooth, tough, pale-yellow skin when ripe and fragrant, white, mucilaginous, translucent, mild-flavored, sweet or insipid pulp containing 1 to 4 oblong seeds, brown, with a pale hilum on one side. Until fully ripe, the fruit is permeated with latex and is very gummy and astringent.

Abiu
Fig. 109: The pale-yellow abiu (Poutertai caimito) as sold in the native market of Buenaventura, Colombia. The fruit is gummy with latex until it becomes fully ripe.

Origin and Distribution

The abiu is a denizen of the headwaters of the Amazon. It grows wild on the lower eastern slopes of the Andes from southwestern Venezuela to Peru. It is often cultivated around Iquitos, Peru. In Ecuador, it is common in the Province of Guayas and the fruits are sold in the markets of Guayaquil. It is much grown around Pará, Brazil; less frequently near Rio de Janeiro, and to a limited extent at Bahia. In Colombia, it is fairly common in the regions of Caquetá, Meta and Vaupés and it abounds in the adjacent areas of Amazonas, Venezuela. It has been growing for many years in Trinidad.

The plant explorers, Dorsett, Shamel and Popenoe, collected seeds for the United States Department of Agriculture in Bahia in 1914 (S.P.I. #37929). In 1915, seeds were received from Lavoras, Minas, Brazil (S.P.I. #41003). This species has been planted several times at the Agricultural Research and Education Center, Homestead, Florida, but most of the young plants have been killed by winter cold. A few trees planted in 1953 fruited in 1962.

Varieties

There is much variation in the form, size and quality of the fruits of seedling trees, some having firm flesh, some soft; and some are insipid, while others have agreeable flavor. At Puerto Ospina, along the Putamayo River in Colombia, there is a type that fruits in 4 years. The fruit is round and large. Near the River Inirida, in Vaupés, Colombia, there is a type that bears in one year from seed, but the fruits are small with little pulp.

Climate

The abiu is strictly tropical or near-tropical. It thrives best in a year-around warm and moist climate, yet Popenoe noted that it does well in somewhat cooler Rio de Janeiro. In Peru it has not been found above 2,000 ft (650 m), though in Colombia, it can be grown up to an elevation of 6,000 ft (1,900 m).

Soil

The tree is naturally suited to fertile, wet soil. It is subject to chlorosis in the limestone of southern Florida.

Season

The fruits are in season in March and April in Ecuador. They are sold in some Brazilian markets from September to April but only a few are seen in the much shorter season of February and March at Bahia. Fruits have matured in October in Florida. The abiu can be picked while underripe and firm for transport to markets.

Propagation and Culture

In Brazil, the washed seeds are dried in the shade and then planted, 3 together and 2 in (5 cm) deep in enriched soil. They will germinate in 15 to 20 days. When the seedlings are 4 in (10 cm) high, the 2 weakest are removed. The strong one is set out when 12 to 16 in (30-40 cm) high. Spacing is 17 x 20 ft (6 x 5 m). One year later, the lower branches are pruned. Fruiting will begin in 3 years; will be substantial in 5 years.

Pests and Diseases

Actually, the fruit has little value commercially because it is commonly damaged by small insects (bichos in Spanish and Portuguese). In Brazil, the chief pests are said to be fruit flies.

Food Uses

In Colombia, people who wish to eat the abiu. are advised to grease their lips beforehand to keep the gummy latex from clinging to them. It is mostly eaten out-of-hand but, in Pará, some types are used to make ices and ice cream.

Food Value Per 100 g of Edible Portion*
Calories 95
Moisture 74.1 g
Protein 2.1 g
Lipids 1.1 g
Glycerides 22.0 g
Fiber 3.0 g
Ash 0.7 g
Calcium 96.0 mg
Phosphorus 45.0 mg
Iron 1.8 mg
Vitamin B, 0.2 mg
Vitamin B2 0.2 mg
Niacin 3.4 mg
Ascorbic Acid 49.0 mg
Amino Acids (mg per g of nitrogen [N 6.25])
Lysine 316 mg
Methionine 178 mg
Threonine 219 mg
Tryptophan 57 mg

*According to analyses made in Brazil.

Other Uses

Wood: The wood is dense and heavy, hard, and valued for construction.

Medicinal Uses: In Brazil, the pulp, because of its mucilaginous nature, is eaten to relieve coughs, bronchitis and other pulmonary complaints. The latex is given as a vermifuge and purge and is applied on abscesses.

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)

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.

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)

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.

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.