Zanmbeel

Monday, May 24, 2010

Alfentanil

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alfentanil may be confused with Anafranil®, fentanyl, remifentanil, sufentanil
Alfenta® may be confused with Sufenta®

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

U.S. BRAND NAMES — Alfenta®

PHARMACOLOGIC CATEGORY
Analgesic, Opioid
Anilidopiperidine Opioid

DOSING: ADULTS — Doses should be titrated to appropriate effects; wide range of doses is dependent upon desired degree of analgesia/anesthesia

Anesthesia: I.V.: Dose should be based on ideal body weight as follows (see table).

Adult Dosage Adjustments

Incremental injection in anesthesia ≤ 30 minutes: Initial dose (induction period): 8-20 mcg/kg Maintenance period (increments/infusion): 3-5 mcg/kg or 0.5-1 mcg/kg/minute Total dose: 8-40 mcg/kg Appropriate effects: Spontaneously breathing or assisted ventilation when required

Incremental injection in anesthesia of 30-60 minutes: Initial dose (induction period): 20-50 mcg/kg Maintenance period (increments/infusion): 5-15 mcg/kg Total dose: Up to 75 mcg/kg Appropriate effects: Assisted or controlled ventilation required. Attenuation of response to laryngoscopy and intubation.

Continuous infusion >45 minutes: Initial dose (induction period): 50-75 mcg/kg Maintenance period (increments/infusion): 0.5-3mcg/kg/minute; average infusion rate: 1-1.5 mcg/kg/minute Total dose: Dependent on duration of procedure Appropriate effects: Assisted or controlled ventilation required. Some attenuation of response to intubation and incision, with intraoperative stability.

Anesthetic induction >45 minutes: Initial dose (induction period): 130-245 mcg/kg Maintenance period (increments/infusion): 0.5-1.5 mcg/kg/minute or general anesthetic Total dose: Dependent on duration of procedure Appropriate effects: Assisted or controlled ventilation required. Administer slowly (over 3 minutes). Concentration of inhalation agents reduced by 30% to 50% for initial hour.

DOSING: PEDIATRIC

(For additional information see "Alfentanil: Pediatric drug information")
Children <12 years: Dose has not been established.

Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

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

Injection, solution [preservative free]: 500 mcg/mL (2 mL, 5 mL)
Alfenta®: 500 mcg/mL (2 mL, 5 mL, 10 mL, 20 mL)

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]: 500 mcg/mL (2 mL, 5 mL)
Alfenta®: 500 mcg/mL (2 mL, 5 mL, 10 mL, 20 mL)

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Administer I.V. slowly over 3-5 minutes or by I.V. continuous infusion.

COMPATIBILITY — Stable in D5W, NS, LR, D5NS.

Y-site administration: Compatible: Cisatracurium, etomidate, gatifloxacin, linezolid, propofol, remifentanil. Incompatible: Amphotericin B cholesteryl sulfate complex, thiopental.

Compatibility in syringe: Compatible: Atracurium, midazolam, ondansetron.

USE — Analgesic adjunct for the induction and maintenance of general anesthesia; analgesic component for monitored anesthesia care (MAC)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Bradycardia, peripheral vasodilation
Central nervous system: Drowsiness, sedation, intracranial pressure increased
Endocrine & metabolic: Antidiuretic hormone release
Gastrointestinal: Nausea, vomiting, constipation
Ocular: Miosis

1% to 10%:
Cardiovascular: Cardiac arrhythmia, orthostatic hypotension
Central nervous system: Confusion, CNS depression
Ocular: Blurred vision

<1% (Limited to important or life-threatening): Convulsions, mental depression, paradoxical CNS excitation or delirium, dizziness, dysesthesia, rash, urticaria, itching, biliary tract spasm, urinary tract spasm, respiratory depression, bronchospasm, laryngospasm, physical and psychological dependence with prolonged use; cold, clammy skin

CONTRAINDICATIONS — Hypersensitivity to alfentanil hydrochloride, to narcotics, or any component of the formulation; increased intracranial pressure, severe respiratory depression

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Opioid agonist toxicities: Shares the toxic potentials of opiate agonists, and precautions of opiate agonist therapy should be observed.

Disease-related concerns: Bradyarrhythmias: Use with caution when administering to patients with bradyarrhythmias. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Obesity: Use with caution in patients who are morbidly obese. Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function.

Special populations: Neonates: Hypotension has occurred in neonates with respiratory distress syndrome. Pediatrics: Safety and efficacy have not been established in children <12 years old.

Other warnings/precautions: Rapid infusion: Inject slowly over 3-5 minutes; rapid I.V. infusion may result in skeletal muscle and chest wall rigidity, impaired ventilation, or respiratory distress/arrest; nondepolarizing skeletal muscle relaxant may be required. Trained individuals: Due to the high incidence of apnea, hypotension, tachycardia and muscle rigidity; it should be administered by individuals specifically trained in the use of anesthetic agents and should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia setting; resuscitative and intubation equipment should be readily available.

RESTRICTIONS — C-II

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major)

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

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

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

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Beta-Blockers: Anilidopiperidine Opioids may enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Anilidopiperidine Opioids may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Anilidopiperidine Opioids may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Alfentanil. Risk C: Monitor therapy

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

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

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

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

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Diltiazem: May increase the serum concentration of Alfentanil. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Alfentanil. Risk D: Consider therapy modification

Fospropofol: Alfentanil may enhance the adverse/toxic effect of Fospropofol. Specifically, the development of opisthotonus (severe hyperextension and spasticity resulting in arching or bridging position) and/or grand mal seizures. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Alfentanil. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

MAO Inhibitors: Anilidopiperidine Opioids may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Avoid use of fentanyl (and other anilidopiperidine opioids when possible) in patients who have used a monoamine oxidase inhibitor within the past 14 days due to reports of unpredictable but severe adverse effects. Risk X: Avoid combination

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

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Propofol: Alfentanil may enhance the adverse/toxic effect of Propofol. Specifically the development of opisthotonus (severe hyperextension and spasticity resulting in arching or bridging position) and/or grand mal seizures. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Alfentanil. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — C (show table)

MONITORING PARAMETERS — Respiratory rate, blood pressure, heart rate

REFERENCE RANGE — 100-340 ng/mL (depending upon procedure)

CANADIAN BRAND NAMES — Alfentanil Injection, USP; Alfenta®

INTERNATIONAL BRAND NAMES — Alfast (BR); Brevafen (AR); Fanaxal (ES); Fentalim (IT); Rapifen (AE, AT, AU, BE, BG, BH, BR, CH, CN, CY, CZ, DE, DK, EG, ES, FI, FR, GB, GR, HK, HN, HR, HU, IE, IL, IQ, IR, IT, JO, KW, LB, LU, LY, NL, NO, OM, PL, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE, ZA)

MECHANISM OF ACTION — Binds with stereospecific receptors at many sites within the CNS, increases pain threshold, alters pain perception, inhibits ascending pain pathways; is an ultra short-acting narcotic

PHARMACODYNAMICS / KINETICS
Onset of action: Rapid

Duration (dose dependent): 30-60 minutes

Distribution: Vd: Newborns, premature: 1 L/kg; Children: 0.163-0.48 L/kg; Adults: 0.46 L/kg

Half-life elimination: Newborns, premature: 5.33-8.75 hours; Children: 40-60 minutes; Adults: 83-97 minutes

Alfentanil

Alendronate and cholecalciferol:

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Fosamax Plus D™ may be confused with Fosamax®

SPECIAL ALERTS
Bisphosphonates: Safety Update Regarding Possible Association With Atrial Fibrillation - November 2008

The Food and Drug Administration (FDA) has been reviewing placebo-controlled trials of the 7 bisphosphonates currently marketed in the US. This review is in response to study results associating an increased incidence of atrial fibrillation (AF) with alendronate or zoledronic acid use in women (65-89 years of age) with osteoporosis.

The FDA reviewed all the submitted data (19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients) from these studies. Overall, the occurrence of AF was rare in each study with an absolute difference in event rates between each of the bisphosphonate and placebo arms of 0-3 per 1000. A zoledronic acid study showed a statistically significant increase in the rate of AF in the active treatment arm. However, no clear association between bisphosphonate use and AF could be established. In this study, AF events were diagnosed more than 30 days after receiving zoledronic acid in 47 of the 50 patients diagnosed with AF. According to the FDA, healthcare providers should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their medication.

The FDA will continue monitoring the safety of bisphosphonates through postmarketing reports and is assessing the need for additional epidemiologic studies.

Further information is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm

U.S. BRAND NAMES — Fosamax Plus D™

PHARMACOLOGIC CATEGORY
Bisphosphonate Derivative
Vitamin D Analog

DOSING: ADULTS — Osteoporosis: Oral: One tablet (alendronate 70 mg/cholecalciferol 2800 int. units or alendronate 70 mg/cholecalciferol 5600 int. units) once weekly. Appropriate dose in most osteoporotic women or men: Alendronate 70 mg/cholecalciferol 5600 int. units once weekly.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Clcr 35-60 mL/minute: No adjustment needed.

Clcr <35 mL/minute: Not recommended.

DOSING: HEPATIC IMPAIRMENT — Alendronate: None necessary. Cholecalciferol: May not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

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

Tablet:
Fosamax Plus D™ 70/2800: Alendronate 70 mg and cholecalciferol 2800 int. units
Fosamax Plus D™ 70/5600: Alendronate 70 mg and cholecalciferol 5600 int. units

DOSAGE FORMS: CONCISE
Tablet:
Fosamax Plus D™ 70/2800: Alendronate 70 mg and cholecalciferol 2800 int. units
Fosamax Plus D™ 70/5600: Alendronate 70 mg and cholecalciferol 5600 int. units

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Alendronate must be taken with plain water (6-8 oz) first thing in the morning and ≥ 30 minutes before the first food, beverage, or other medication of the day. Patient should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation).

USE — Treatment of osteoporosis in postmenopausal females; increase bone mass in males with osteoporosis

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to alendronate, other bisphosphonates, vitamin D derivatives, or any component of the formulation; hypocalcemia; abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Bone/joint/muscle pain: Severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy. Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use if new or worsening symptoms develop. Osteonecrosis of the jaw: Bisphosphonate therapy has been associated with osteonecrosis, primarily of the jaw; this has been observed mostly in cancer patients, but also in patients with postmenopausal osteoporosis and other diagnoses. Risk factors include a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection or pre-existing dental disease. Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. Symptoms included nonhealing extraction socket or an exposed jawbone. There are no data addressing whether discontinuation of therapy reduces the risk of developing osteonecrosis. However, as a precautionary measure, dental exams and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. Invasive dental procedures should be avoided during treatment.

Disease-related concerns: Gastrointestinal malabsorption syndrome: Increased doses of vitamin D supplementation may be required in patients with GI malabsorption syndrome; consider monitoring 25-hydroxy vitamin D levels. Hypercalcemia: May exacerbate hypercalcemia and/or hypercalciuria in certain disease states (eg, leukemia, lymphoma, sarcoidosis); monitor serum and urine calcium levels. Hypocalcemia/vitamin D deficiency: Before therapy initiation hypocalcemia and/or vitamin D deficiency must be corrected; ensure adequate calcium and vitamin D intake. Do not use to treat vitamin D deficiency. Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with Clcr <35 mL/minute).

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

DRUG INTERACTIONS
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Antacids: May decrease the absorption of Bisphosphonate Derivatives. Antacids containing aluminum, calcium, or magnesium are of specific concern. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy

Calcium Salts: May decrease the absorption of Bisphosphonate Derivatives. Risk D: Consider therapy modification

Iron Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral iron salts are of concern. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification

Magnesium Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral magnesium salts are of concern. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy

Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Animal studies have shown delays in delivery and fetal/neonatal death (secondary to hypocalcemia). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. No animal data are available for the use of cholecalciferol in pregnancy; however, high-dose ergocalciferol has demonstrated abortifacient properties and aortic abnormalities in rabbits. There are no adequate and well-controlled studies in pregnant women.

LACTATION — Cholecalciferol enters breast milk; excretion of alendronate in breast milk unknown/use caution

DIETARY CONSIDERATIONS — Ensure adequate calcium and vitamin D intake; supplemental calcium should be provided in patients whose dietary intake is inadequate. Recommended intake of vitamin D is 400-800 int. units daily. Certain patients may require additional vitamin D supplementation, particularly patients at risk for vitamin D deficiency (eg, malabsorption syndromes, chronically ill, >70 years of age). Consider monitoring 25-hydroxy vitamin D in patients with malabsorption syndromes. Wait at least 30 minutes after taking alendronate with cholecalciferol before taking any supplement. Must be taken with at least 6-8 oz. plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Administer with plain water only; do not administer with mineral-enriched water.

PRICING — (data from drugstore.com)
Tablets (Fosamax Plus D)
70-2800 mg-unit (4): $93.00
70-5600 mg-unit (4): $91.93

MONITORING PARAMETERS — Alkaline phosphatase (measured periodically); urine and serum calcium, serum phosphorus, serum 25-hydroxy vitamin D; monitor pain and fracture rate; hormonal status (male and female) prior to therapy; bone mineral density (should be done prior to initiation of therapy and after 6-12 months of combined glucocorticoid and alendronate treatment)

REFERENCE RANGE
Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging

Phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)

25-hydroxyvitamin D: 10-80 ng/mL (higher during summer)

CANADIAN BRAND NAMES — Fosavance

INTERNATIONAL BRAND NAMES — Adrovance (FR); Fosamax Plus (AR, CN, CO, CR, EC, GT, HK, HN, ID, KP, MX, MY, NI, NZ, PA, SG, SV, TH, TW); Fosavance (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PH, PT, RU, SE, TR); Maximus (PE)

MECHANISM OF ACTION — See individual agents.

PATIENT INFORMATION — Do not take more than the recommended amount. While taking this medication, your prescriber may want you to follow a special diet or take a calcium supplement. Follow this diet closely. Avoid taking magnesium supplements or magnesium-containing antacids. Early symptoms of hypercalcemia include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, cramps, diarrhea, muscle pain, bone pain, and irritability.

Alendronate and cholecalciferol:

Alendronate:

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alendronate may be confused with risedronate
Fosamax® may be confused with Flomax®, Fosamax Plus D™ , fosinopril, Zithromax®

International issues:
Fosamax® may be confused with Fisamox® which is a brand name for amoxicillin in Australia

SPECIAL ALERTS
Bisphosphonates: Safety Update Regarding Possible Association With Atrial Fibrillation - November 2008

The Food and Drug Administration (FDA) has been reviewing placebo-controlled trials of the 7 bisphosphonates currently marketed in the US. This review is in response to study results associating an increased incidence of atrial fibrillation (AF) with alendronate or zoledronic acid use in women (65-89 years of age) with osteoporosis.

The FDA reviewed all the submitted data (19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients) from these studies. Overall, the occurrence of AF was rare in each study with an absolute difference in event rates between each of the bisphosphonate and placebo arms of 0-3 per 1000. A zoledronic acid study showed a statistically significant increase in the rate of AF in the active treatment arm. However, no clear association between bisphosphonate use and AF could be established. In this study, AF events were diagnosed more than 30 days after receiving zoledronic acid in 47 of the 50 patients diagnosed with AF. According to the FDA, healthcare providers should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their medication.

The FDA will continue monitoring the safety of bisphosphonates through postmarketing reports and is assessing the need for additional epidemiologic studies.

Further information is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm

U.S. BRAND NAMES — Fosamax®

PHARMACOLOGIC CATEGORY
Bisphosphonate Derivative

DOSING: ADULTS — Note: Patients treated with glucocorticoids and those with Paget's disease should receive adequate amounts of calcium and vitamin D.

Osteoporosis in postmenopausal females: Oral:
Prophylaxis: 5 mg once daily or 35 mg once weekly
Treatment: 10 mg once daily or 70 mg once weekly

Osteoporosis in males: Oral: 10 mg once daily or 70 mg once weekly

Osteoporosis secondary to glucocorticoids in males and females: Oral: Treatment: 5 mg once daily; a dose of 10 mg once daily should be used in postmenopausal females who are not receiving estrogen.

Paget's disease of bone in males and females: Oral: 40 mg once daily for 6 months
Retreatment: Relapses during the 12 months following therapy occurred in 9% of patients who responded to treatment. Specific retreatment data are not available. Following a 6-month post-treatment evaluation period, treatment with alendronate may be considered in patients who have relapsed based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Clcr 35-60 mL/minute: None necessary.

Clcr <35 mL/minute: Alendronate is not recommended due to lack of experience.

DOSING: HEPATIC IMPAIRMENT — No adjustment necessary.

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

Solution, oral:
Fosamax®: 70 mg/75 mL [contains parabens; raspberry flavor]

Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg

DOSAGE FORMS: CONCISE
Solution, oral:
Fosamax®: 70 mg/75 mL

Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg

GENERIC EQUIVALENT AVAILABLE — Yes: Tablet

ADMINISTRATION — Alendronate must be taken with plain water (tablets 6-8 oz; oral solution follow with 2 oz) first thing in the morning and ≥ 30 minutes before the first food, beverage, or other medication of the day. Do not take with mineral water or with other beverages. Patients should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation). Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

USE — Treatment and prevention of osteoporosis in postmenopausal females; treatment of osteoporosis in males; Paget's disease of the bone in patients who are symptomatic, at risk for future complications, or with alkaline phosphatase ≥ 2 times the upper limit of normal; treatment of glucocorticoid-induced osteoporosis in males and females with low bone mineral density who are receiving a daily dosage ≥ 7.5 mg of prednisone (or equivalent)

ADVERSE REACTIONS SIGNIFICANT — Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget's disease at 40 mg/day.

>10%: Endocrine & metabolic: Hypocalcemia (transient, mild, 18%); hypophosphatemia (transient, mild, 10%)

1% to 10%:
Cardiovascular: Atrial fibrillation (1% to 2%)
Central nervous system: Headache (up to 3%)
Gastrointestinal: Abdominal pain (1% to 7%), acid reflux (1% to 4%), dyspepsia (1% to 4%), nausea (1% to 4%), flatulence (up to 4%), diarrhea (1% to 3%), gastroesophageal reflux disease (1% to 3%), constipation (up to 3%), esophageal ulcer (up to 2%), abdominal distension (up to 1%), gastritis (up to 1%), vomiting (up to 1%), dysphagia (up to 1%), gastric ulcer (1%), melena (1%)
Neuromuscular & skeletal: Musculoskeletal pain (up to 6%), muscle cramps (up to 1%)

<1% (Limited to important or life-threatening): Alopecia, anastomotic ulcer, angioedema; bone, muscle, or joint pain (occasionally severe, considered incapacitating in rare cases); dizziness, duodenal ulcer, episcleritis, erythema, esophageal cancer, esophageal erosions, esophageal perforation, esophageal stricture, esophagitis, fever, flu-like syndrome, hypersensitivity reactions, hypocalcemia (symptomatic), joint swelling, lymphocytopenia, malaise, myalgia, oropharyngeal ulceration, osteonecrosis (jaw), peripheral edema, photosensitivity (rare), pruritus, rash, scleritis (rare), Stevens-Johnson syndrome, taste perversion, toxic epidermal necrolysis, urticaria, uveitis (rare), vertigo, weakness

CONTRAINDICATIONS — Hypersensitivity to alendronate, other bisphosphonates, or any component of the formulation; hypocalcemia; abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes; oral solution should not be used in patients at risk of aspiration

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Bone/joint/muscle pain: Severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy. Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use if new or worsening symptoms develop. Hypocalcemia: Hypocalcemia has been reported with the use of bisphosphonates. Prior to therapy initiation, hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake. Osteonecrosis of the jaw: Bisphosphonate therapy has been associated with osteonecrosis, primarily of the jaw; this has been observed mostly in cancer patients, but also in patients with postmenopausal osteoporosis and other diagnoses. Risk factors include a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection, or pre-existing dental disease. Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. Symptoms included nonhealing extraction socket or an exposed jawbone. There are no data addressing whether discontinuation of therapy reduces the risk of developing osteonecrosis; however, as a precautionary measure, dental exams and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. Invasive dental procedures should be avoided during treatment.

Disease-related concerns: Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with Clcr <35 mL/minute).

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

DRUG INTERACTIONS
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Antacids: May decrease the absorption of Bisphosphonate Derivatives. Antacids containing aluminum, calcium, or magnesium are of specific concern. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy

Calcium Salts: May decrease the absorption of Bisphosphonate Derivatives. Risk D: Consider therapy modification

Iron Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral iron salts are of concern. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification

Magnesium Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral magnesium salts are of concern. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor therapy

Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Avoid ethanol (may increase risk of osteoporosis and gastric irritation).

Food: All food and beverages interfere with absorption. Coadministration with caffeine may reduce alendronate efficacy. Coadministration with dairy products may decrease alendronate absorption. Beverages (especially orange juice and coffee) and food may reduce the absorption of alendronate as much as 60%.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Safety and efficacy have not been established in pregnant women. Animal studies have shown delays in delivery and fetal/neonatal death (secondary to hypocalcemia). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. Based on limited case reports with pamidronate, serum calcium levels in the newborn may be altered if administered during pregnancy.

LACTATION — Excretion in breast milk unknown/use caution

DIETARY CONSIDERATIONS — Ensure adequate calcium and vitamin D intake; women >50 years of age should consume 1200-1500 mg/day of elemental calcium and 800-1000 int. units/day of vitamin D. Wait at least 30 minutes after taking alendronate before taking any supplement. Alendronate must be taken with plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day.

PRICING — (data from drugstore.com)
Solution (Fosamax)
70 mg/75 mL (75): $33.13

Tablets (Alendronate Sodium)
5 mg (100): $255.98
10 mg (100): $234.99
35 mg (4): $49.99
40 mg (30): $179.99
70 mg (4): $32.99

Tablets (Fosamax)
5 mg (30): $91.92
10 mg (30): $95.12
35 mg (4): $87.65
70 mg (4): $93.00

MONITORING PARAMETERS — Alkaline phosphatase should be periodically measured; serum calcium and phosphorus; monitor pain and fracture rate; hormonal status (male and female) prior to therapy; bone mineral density (should be done prior to initiation of therapy and after 6-12 months of combined glucocorticoid and alendronate treatment)

REFERENCE RANGE — Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging; phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)

CANADIAN BRAND NAMES — Apo-Alendronate®; CO Alendronate; Dom-Alendronate; Fosamax®; Gen-Alendronate; Novo-Alendronate; PHL-Alendronate; PHL-Alendronate-FC; PMS-Alendronate; PMS-Alendronate-FC; ratio-Alendronate; Riva-Alendronate; Sandoz Alendronate

INTERNATIONAL BRAND NAMES — Aldrox (CN); Alenato (AR); Alend (KP); Alendro (AU); Alendros (KP); Alenmax (KP); Alnax (PY); Alond (KP); Alovell (ID); Arendal (PE); Armol (CO); Bifemelan (CO); Bifosa (IN); Bisbon (KP); Bonapex (EG); Endronax (BR); Eucalen (CO); Fixopan (EC); Fosalan (IL); Fosamax (AR, AT, AU, BB, BE, BG, BM, BR, BS, BZ, CH, CL, CN, CR, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, GT, GY, HK, HN, ID, IE, IT, JM, MX, MY, NI, NL, NO, PA, PE, PH, PK, PT, SE, SG, SR, SV, TH, TT, TW, VE); Fosaqueen (KP); Fosmin (PE); Fosval (PY); Gendarin (SE); Marvil (PE, UY); MaxiBone (IL); MaxiBone 70 (IL); Neobon (CO); Nichospor (ID); Oseotenk (AR); Osficar (CO); Osteofar (ID); Osteofos (HK, IN); Osteopor (UY); Osteosan (CN); Osteovan (CR); Porosal (VE); Tevanate (BG); Voroste (ID)

MECHANISM OF ACTION — A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget's disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.

PHARMACODYNAMICS / KINETICS
Distribution: 28 L (exclusive of bone)

Protein binding: ~78%

Metabolism: None

Bioavailability: Fasting: 0.6%; reduced 60% with food or drink

Half-life elimination: Exceeds 10 years

Excretion: Urine; feces (as unabsorbed drug)

PATIENT INFORMATION — Take as directed, with a full glass of water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Wait at least 30 minutes after taking alendronate before taking anything else. Stay in sitting or standing position for 30 minutes following administration and until after the first food of the day to reduce potential for esophageal irritation. Consult prescriber to determine necessity of lifestyle changes (eg, decreased smoking, decreased alcohol intake, dietary supplements of calcium, or increased dietary vitamin D

Alendronate:

Alemtuzumab

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

SPECIAL ALERTS
Alemtuzumab: Reports of Infection-Related Fatalities - November 2008

Bayer HealthCare and Genzyme, in conjunction with Health Canada, have issued notice to Canadian hospitals concerning reports of infection-related fatalities in patients receiving consolidation therapy with MabCampath® (alemtuzumab). Preliminary safety data from the ongoing phase II U.S. clinical trial CALGB10101 has reported fatalities in 6 out of 51 patients with B-cell chronic lymphocytic leukemia (B-CLL) receiving fludarabine and rituximab induction therapy followed by alemtuzumab therapy for remission consolidation.

Fatal infections included viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and Epstein-Barr virus (EBV) associated lymphoproliferative disorder.

The potential contributory role of any of the three chemotherapeutic agents is not clear based on available data. The infectious complications may have resulted from prolonged immunosuppression. An additional noninfection-related fatality, thought to be transfusion-associated graft-versus-host disease (TAGVHD), has also been reported.

Use of alemtuzumab as consolidation therapy is presently not approved in Canada. An updated product monograph including this new important safety information is forthcoming. Further information can be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/mabcampath_nth-aah-eng.php

U.S. BRAND NAMES — Campath®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Monoclonal Antibody

DOSING: ADULTS — Note: Dose escalation is required; usually accomplished in 3-7 days. Single doses >30 mg or cumulative doses >90 mg/week increase the incidence of pancytopenia. Pretreatment (with acetaminophen and diphenhydramine) is recommended prior to the first dose, with dose escalations, and as clinically indicated; I.V. hydrocortisone may be used for severe infusion-related reactions. Reinitiate with gradual dose escalation if treatment is withheld ≥ 7 days.

B-cell CLL:
I.V. infusion: Initial: 3 mg/day beginning on day 1; if tolerated (infusion reaction ≤ grade 2), increase to 10 mg/day; if tolerated (infusion reaction ≤ grade 2), increase to maintenance of 30 mg/dose 3 times/week on alternate days for a total duration of therapy of up to 12 weeks
SubQ (unlabeled route): Initial: 3 mg on day 1; if tolerated 10 mg on day 3; if tolerated increase to 30 mg on day 5; maintenance: 30 mg/dose 3 times/week for a maximum of 18 weeks (Lundin, 2002) or 3 mg on day 1; if tolerated 10 mg on day 2; if tolerated 30 mg on day 3, followed by 30 mg/dose 3 times/week for 4-12 weeks (Stilgenbauer, 2009)

Cutaneous T-cell lymphoma (unlabeled use): I.V. infusion: 3 mg on day 1; if tolerated increase the next dose to 10 mg; if tolerated increase the next dose to 30 mg; Maintenance dose: 30 mg/dose 3 times/week for up to 12 weeks (Lundin, 2003)

Peripheral T-cell lymphoma (unlabeled use):I.V. infusion: 3 mg on day 1; 10 mg on day 3, followed by 30 mg/dose 3 times/week for a duration of therapy of up to 12 weeks (Enblad, 2004)

T-cell prolymphocytic leukemia (unlabeled use):I.V. infusion: Initial test dose 3 mg or 10 mg, followed by dose escalation to 30 mg/dose 3 times/week as tolerated (Dearden, 2001)
or
Week 1: 3 mg on day 1; 10 mg on day 2; 30 mg on day 3, followed in subsequent weeks by 30 mg/dose on alternate days 3 times/week for a total of 4-12 weeks (Ferrajoli, 2003)
or
Initial dose: 3 mg day 1, if tolerated increase to 10 mg day 2, if tolerated increase to 30 mg on day 3 (days 1, 2, and 3 are consecutive days), followed by 30 mg/dose every Monday, Wednesday, Friday for a total of 4-12 weeks (Keating, 2002)

DOSING: ELDERLY — Refer to adult dosing.

DOSING: ADJUSTMENT FOR TOXICITY
Dosage adjustment for nonhematologic toxicity:
Grade 3 or 4 infusion reaction: Withhold infusion.
Serious infection or other serious adverse reaction: Withhold alemtuzumab until resolution.
Autoimmune anemia or autoimmune thrombocytopenia: Discontinue alemtuzumab.

Dosage adjustment for hematologic toxicity (severe neutropenia or thrombocytopenia, not autoimmune):
First occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Hold therapy; resume at 30 mg/dose when ANC ≥ 500/µL and platelet count ≥ 50,000/µL.
Second occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Hold therapy; resume at 10 mg/dose when ANC ≥ 500/µL and platelet count ≥ 50,000/µL.
Third occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Discontinue alemtuzumab.
Patients with a baseline ANC ≤ 250/µL and/or a baseline platelet count ≤ 25,000/µL at initiation of therapy: If ANC and/or platelet counts decrease to ≤ 50% of the baseline value, hold therapy.
First occurrence: When ANC and/or platelet count return to baseline, resume therapy at 30 mg/dose.
Second occurrence: When ANC and/or platelet count return to baseline, resume therapy at 10 mg/dose.
Third occurrence: Discontinue alemtuzumab.

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

Injection, solution [preservative free]:
Campath®: 30 mg/mL (1 mL) [contains polysorbate 80; disodium edetate]

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Campath®: 30 mg/mL (1 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer by I.V. infusion over 2 hours. Consider premedicating with diphenhydramine 50 mg and acetaminophen 500-1000 mg 30 minutes before initiation of infusion. Hydrocortisone 200 mg has been effective in decreasing severe infusion-related events. Start anti-infective prophylaxis. Other drugs should not be added to or simultaneously infused through the same I.V. line. Do not give I.V. push.

SubQ (unlabeled route): SubQ administration has been studied (Lundin, 2002; Stilgenbauer, 2009); an increased rate of injection site reactions has been observed, with only rare incidences of chills or infusion-like reactions typically observed with I.V. infusion. A longer dose escalation time (1-2 weeks) may be needed due to injection site reactions (Lundin, 2002). Premedication and anti-infective prophylaxis regimens should be given as are recommended with I.V. administration.

COMPATIBILITY — Stable in D5W, NS. Medications should not be added to the solution or simultaneously infused through the same I.V. line.

USE — Treatment of B-cell chronic lymphocytic leukemia (B-CLL)

USE - UNLABELED / INVESTIGATIONAL — Treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, refractory T-cell prolymphocytic leukemia, refractory or resistant autoimmune cytopenias; preconditioning regimen and prophylaxis of graft-versus-host disease (GVHD) in allogeneic stem cell transplant; immunosuppressant in solid organ transplant (induction and rejection)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Hypotension (15% to 32%), peripheral edema (13%), hypertension (11% to 15%), dysrhythmia/tachycardia/SVT (10% to 14%)
Central nervous system: Fever (69% to 85%), chills (53%), fatigue (22% to 34%), headache (13% to 24%), dysthesias (15%), dizziness (12%)
Dermatologic: Rash (13% to 40%), urticaria (16% to 30%), pruritus (14% to 24%)
Gastrointestinal: Nausea (47% to 54%), vomiting (33% to 41%), anorexia (20%), diarrhea (10% to 22%), stomatitis/mucositis (14%), abdominal pain (11%)
Hematologic: Lymphopenia (grades 3/4: 97%), neutropenia (77% to 85%; grade 3/4: 42% to 70% [median onset: 31 days, median duration: 28-37 days]), anemia (76% to 80%; grade 3/4: 12% to 47% [median onset: 31 days, median duration 8 days]), thrombocytopenia (71% to 72%; grade 3/4: 13% to 52% [median onset: 9 days; median duration: 14-21 days])
Local: Injection site reaction (SubQ administration: 90%)
Neuromuscular & skeletal: Rigors (86% to 89%), skeletal pain (24%), weakness (13%), myalgia (11%)
Respiratory: Dyspnea (14% to 26%), cough (25%), bronchitis/pneumonitis (21%), pneumonia (16%), pharyngitis (12%)
Miscellaneous: Infection (43% to 74%; grades 3/4: 21% to 37%; incidence is lower if prophylactic anti-infectives are utilized), CMV viremia (55%), infusion reactions (grades 3/4: 10% to 35%), diaphoresis (19%), CMV infection (6% to 16%), sepsis (15%; grades 3/4: 3% to 10%), herpes viral infections (1% to 11%)

1% to 10%:
Cardiovascular: Chest pain (10%)
Central nervous system: Insomnia (10%), malaise (9%), anxiety (8%), depression (7%), temperature change sensation (5%), somnolence (5%)
Dermatologic: Purpura (8%), erythema (4%)
Gastrointestinal: Dyspepsia (10%), constipation (9%)
Hematologic: Neutropenic fever (10%; grades 3/4: 5% to 10%), pancytopenia/marrow hypoplasia (5% to 6%; grade 3/4: 3%), positive Coombs' test without hemolysis (2%), autoimmune thrombocytopenia (2%), autoimmune hemolytic anemia (1%)
Neuromuscular & skeletal: Back pain (10%), tremor (3% to 7%)
Respiratory: Bronchospasm (9%), epistaxis (7%), rhinitis (7%)
Miscellaneous: Moniliasis (8%)

<1% (Limited to important or life-threatening): Acidosis, acute renal failure, acute respiratory distress syndrome, agranulocytosis, alkaline phosphatase increased, allergic reactions, anaphylactoid reactions, angina pectoris, angioedema, anuria, aphasia, aplastic anemia, arrhythmia, ascites, asthma, atrial fibrillation, bacterial infection, biliary pain, bone marrow aplasia, bullous eruption, capillary fragility, cardiac arrest, cardiac failure, cardiac insufficiency, cardiomyopathy, cellulitis, cerebral hemorrhage, cerebrovascular disorder, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), coagulation abnormality, colitis, coma, COPD, coronary artery disorder, cyanosis, deep vein thrombosis, dehydration, diabetes mellitus exacerbation, disseminated intravascular coagulation (DIC), duodenal ulcer, ejection fraction decreased, endophthalmitis, Epstein-Barr virus associated lymphoproliferative disorder, esophagitis, fluid overload, flu-like syndrome, gastrointestinal hemorrhage, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, hallucinations, hematemesis, hematoma, hematuria, hemolysis, hemolytic anemia, hemoptysis, hepatic failure, hepatocellular damage, HF, hyperbilirubinemia, hyper-/hypoglycemia, hyper-/hypokalemia, hypersensitivity, hyperthyroidism, hypoalbuminemia, hyponatremia, hypovolemia, hypoxia, idiopathic thrombocytopenic purpura (ITP), interstitial pneumonitis, intestinal obstruction, intestinal perforation, intracranial hemorrhage, Legionella pneumonia, Listeria meningitis, lymphadenopathy, marrow depression, melena, MI, mouth edema, myositis, optic neuropathy, osteomyelitis, pancreatitis, paralysis, paralytic ileus, paroxysmal nocturnal hemoglobinuria-like monocytes, peptic ulcer, pericarditis, peritonitis, plasma cell dyscrasia, phlebitis, pleural effusion, pleurisy, Pneumocystis jiroveci pneumonia, pneumothorax, polymyositis, progressive multifocal leukoencephalopathy, pseudomembranous colitis, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary infiltration, pure red cell aplasia, purpuric rash, renal dysfunction, respiratory alkalosis, respiratory arrest, respiratory depression, respiratory insufficiency, seizure (grand mal), serum sickness, sinus bradycardia, splenic infarction, splenomegaly, stridor, subarachnoid hemorrhage, syncope, toxic nephropathy, thrombocythemia, thrombophlebitis, throat tightness, transfusion-associated GVHD, tuberculosis, tumor lysis syndrome, ureteric obstruction, urinary retention, urinary tract infection, ventricular arrhythmia, ventricular tachycardia, viral meningitis, virus reactivation (latent)

CONTRAINDICATIONS — There are no contraindications listed in the manufacturer's labeling

WARNINGS / PRECAUTIONS
Boxed warnings: Hematologic toxicity: See "Concerns related to adverse effects" below. Infections: See "Concerns related to adverse effects" below. Infusion reactions: See "Concerns related to adverse effects" below.

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

Concerns related to adverse effects: Hematologic toxicity: [U.S. Boxed Warning]: Serious and fatal cytopenias (including pancytopenia, bone marrow hypoplasia, autoimmune hemolytic anemia, and autoimmune idiopathic thrombocytopenia) have occurred. Single doses >30 mg or cumulative weekly doses >90 mg are associated with an increased incidence of pancytopenia. Severe prolonged myelosuppression, hemolytic anemia, pure red cell aplasia, and bone marrow aplasia have also been reported. Discontinue therapy during serious hematologic or other serious toxicity (except lymphopenia) until the event resolves. Permanently discontinue if autoimmune anemia or autoimmune thrombocytopenia occurs. Patients receiving blood products should only receive irradiated blood products due to the potential for transfusion-associated GVHD during lymphopenia. Infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (bacterial, viral, fungal, and protozoan) have been reported. Prophylactic medications against PCP pneumonia and herpes viral infections are recommended upon initiation of therapy and for at least 2 months following last dose or until CD4+ counts are ≥ 200 cells/µL (whichever is later). Severe and prolonged lymphopenia may occur; CD4+ counts usually return to ≥ 200 cells/µL within 2-6 months; however, CD4+ and CD8+ lymphocyte counts may not return to baseline levels for more than 1 year. Withhold treatment during serious infections; may be reinitiated upon resolution of infection. Monitor for CMV infection (during and for at least 2 months after completion of therapy); initiate appropriate antiviral treatment and withhold alemtuzumab for CMV infection or confirmed CMV viremia (withhold alemtuzumab during CMV antiviral treatment). Infusion reactions: [U.S. Boxed Warning]: Serious and potentially fatal infusion-related reactions may occur; withhold treatment for grade 3 or 4 infusion reactions. Gradual escalation to the recommended maintenance dose is required at initiation and with therapy interruption (for ≥ 7 days) to minimize infusion-related reactions. Infusion reaction symptoms may include acute respiratory distress syndrome, anaphylactic shock, angioedema, bronchospasm, cardiac arrest, cardiac arrhythmias, chills, dyspnea, fever, hypotension, myocardial infarction, pulmonary infiltrates, rash, rigors, syncope, or urticaria. The incidence of infusion reaction is highest during the first week of treatment. Premedication with acetaminophen and an oral antihistamine is recommended. Medications for the treatment of reactions should be available for immediate use. Use caution and carefully monitor blood pressure in patients with ischemic heart disease and patients on antihypertensive therapy. Reinitiate with gradual dose escalation if treatment is withheld ≥ 7 days.

Special populations: Men of reproductive potential: Should use effective contraceptive methods during treatment and for a minimum of 6 months following therapy. Pediatrics: Safety and efficacy have not been established in children. Women of childbearing potential: Should use effective contraceptive methods during treatment and for a minimum of 6 months following therapy.

Other warnings/precautions: Immunizations: Patients should not be immunized with live, viral vaccines during or recently after treatment. The ability to respond to any vaccine following therapy is unknown.

DRUG INTERACTIONS
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. 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

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Echinacea may diminish the therapeutic effect of alemtuzumab.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Human IgG is known to cross the placental barrier; therefore, alemtuzumab may also cross the barrier and cause fetal B- and T-lymphocyte depletion. Well-controlled human trials have not been done. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Effective contraception is recommended during and for 6 months after treatment for women of childbearing potential and men of reproductive potential.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Human IgG is excreted in breast milk; therefore, alemtuzumab may also be excreted in milk. Breast-feeding should be discontinued during treatment and for at least 3 months following the last dose.

PRICING — (data from drugstore.com)
Solution (Campath)
30 mg/mL (3): $5999.53

MONITORING PARAMETERS — Vital signs; carefully monitor BP especially in patient with ischemic heart disease or on antihypertensive medications; CBC with differential and platelets (weekly, more frequent if worsening); signs and symptoms of infection; CD4+ lymphocyte counts (after treatment until recovery); CMV antigen (every 1-2 weeks). Monitor closely for infusion reactions (including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash).

CANADIAN BRAND NAMES — MabCampath®

INTERNATIONAL BRAND NAMES — Campath (AR, PE, UY); MabCampath (AT, AU, BE, BG, CH, CO, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, ID, IE, IL, IT, KP, MY, NL, NO, PT, RU, SE, SG, TR, ZA); Mabcampath (PL)

MECHANISM OF ACTION — Binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. After binding to CD52+ cells, an antibody-dependent lysis of leukemic cells occurs.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: I.V.: 0.1-0.4 L/kg

Metabolism: Clearance decreases with repeated dosing (due to loss of CD52 receptors in periphery), resulting in a sevenfold increase in AUC.

Half-life elimination: I.V.: 11 hours (following first 30 mg dose; range: 2-32 hours); 6 days (following the last 30 mg dose; range: 1-14 days)

PATIENT INFORMATION — You will need frequent laboratory tests during course of therapy. Do not use any prescription or OTC medications unless approved by your prescriber. Maintain adequate hydration (2-3 L/day unless otherwise instructed) and nutrition (frequent small meals will help). You may experience abdominal pain, mouth sores, nausea, or vomiting (small frequent meals, good mouth care with soft toothbrush or swabs, sucking lozenges or chewing gum, and avoidance of spicy or salty foods may help). Report unresolved gastrointestinal problems, persistent fever, chills, muscle pain, skin rash, unusual bleeding or bruising, signs of infection (mouth sores, sore throat, white plaques in mouth or perianal area, burning on urination); swelling of extremities; difficulty breathing; chest pain or palpitations; or other persistent adverse reactions.

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Monday, May 24, 2010