Aredia

Generic Name: Pamidronate Disodium
Class: Bone Resorption Inhibitors
VA Class: HS900
Chemical Name: (3-Amino-1-hydroxypropylidene)bisphosphonic acid disodium salt pentahydrate
Molecular Formula: C₃H_9NNa₂O₇P₂•5H₂O
CAS Number: 109552-15-0

Special Alerts:

[Posted 10/13/2010] ISSUE: FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including alendronate (Fosamax), alendronate with cholecalciferol (Fosamax Plus D), risedronate (Actonel and Atelvia), risedronate with calcium carbonate (Actonel with Calcium), ibandronate (Boniva), tiludronate (Skelid), and zoledronic acid (Reclast) and their generic products. A Medication Guide will also be required to be given to patients when they pick up their bisphosphonate prescription.

BACKGROUND: Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in patients taking bisphosphonates.

RECOMMENDATIONS: Patients should continue to take their medication unless told to stop by their healthcare professional. FDA recommends that healthcare professionals should discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. For more information visit the FDA website at: and .

[Posted 03/11/2010] FDA notified healthcare professionals and patients that at this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.

FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing oral bisphosphonates.

Patients should continue taking oral bisphosphonates unless told by their healthcare professional to stop. Patients should talk to their healthcare professional if they develop new hip or thigh pain or have any concerns with their medications. For more information visit the FDA website at: and .

[Posted 11/12/2008] FDA issued an update to the Agency’s review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. For more information visit the FDA website at: , and .

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

[Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.

Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: and .

[Posted 10/01/2007] FDA issued an early communication about the ongoing review of new safety data regarding the association of atrial fibrillation with the use of bisphosphonates. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, treat bone metastases, and lower elevated levels of blood calcium in patients with cancer.

FDA reviewed spontaneous postmarketing reports of atrial fibrillation reported in association with oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of once-yearly Reclast for the treatment of postmenopausal osteoporosis, FDA evaluated the possible association between atrial fibrillation and the use of Reclast (zoledronic acid). Most cases of atrial fibrillation occurred more than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the 11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation between patients who received Reclast and patients who received placebo.

Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time. For more information visit the FDA website at: and .

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.^{1 3 4 5}

Uses for Aredia

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hypercalcemia Associated with Malignancy

Used in conjunction with achievement and maintenance of adequate hydration for the treatment of moderate to severe hypercalcemia associated with malignant neoplasms, with or without bone metastases^{1 3 4 5}

Retreatment may be considered in patients with recurrent or refractory disease.¹

Paget’s Disease of Bone

Treatment of moderate to severe Paget’s disease of bone (osteitis deformans)^{1 6 7 8 9 11 13 15 16 25 26 40 15} in symptomatic patients with multiple bone involvement [polyostotic] and elevated concentrations of serum alkaline phosphatase and urinary hydroxyproline.^{7 8 13 20}

May prevent or slow progression of complications (e.g., deformities, arthritis, fractures, neurologic manifestations, spinal cord compression, heart failure) in patients with Paget’s Disease.^{11 26 40} May not reverse established complications (e.g., severe deformities, deafness).^{11 26 40}

Treatment in patients refractory to calcitonin or etidronate disodium.^{8 9 11 13 16}

Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

Decreases the incidence and delays the development of bone-related complications (e.g., fractures or spinal cord compression, bone deterioration requiring radiotherapy or orthopedic surgery), and reduces bone pain and the need for supplemental analgesic therapy in patients with osteolytic metastases associated with breast cancer^{1 23 24 27} and in patients with osteolytic lesions of multiple myeloma.^{1 29}

Used as an adjunct to antineoplastic therapy for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma.^{1 20 29}

Aredia Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Monitor standard laboratory and clinical parameters of renal function (including serum creatinine) and complete blood counts with differential and hematocrit and hemoglobin.¹

  
  


• 
  

  Carefully monitor standard hypercalcemia-related metabolic parameters (e.g., serum concentrations of calcium, phosphate, magnesium, and potassium) following initiation of therapy.¹

  
  

Hypercalcemia Associated with Malignancy

• 
  

  Adequately hydrate patients prior to treatment initiation and throughout treatment.¹ Avoid overhydration, especially in patients at risk for the development of cardiac failure.¹ Attempt to restore urine output to 2L/day throughout treatment.¹

  
  


• 
  

  Corticosteroid therapy may prove beneficial.¹

  
  

Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

• 
  

  Adequately hydrate patients with osteolytic lesions of multiple myeloma and marked Bence-Jones proteinuria with 0.9% sodium chloride prior to treatment initiation.^{1 39}

  
  

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

IV Administration

Administer by IV infusion.^{1 3 4 5 8 11 14 16 20 23 24 26 27 29 40}

Reconstitution

Reconstitute vial containing 30 or 90 mg of pamidronate disodium with 10 mL of sterile water for injection to provide a solution containing 3 or 9 mg /mL, respectively.¹

Allow the contents of the vials to dissolve completely before withdrawing a dose.¹

Dilution

Hypercalcemia Associated with Malignancy

Dilute the recommended daily dose in 1 L of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection.¹

Paget’s Disease of Bone

Dilute 30 mg in 500 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection.¹

Osteolytic Bone Metastases of Breast Cancer

Dilute 90 mg in 250 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection.¹

Osteolytic Lesions of Multiple Myeloma

Dilute 90 mg in 500 mL of 0.45 or 0.9% sodium chloride injection or 5% dextrose injection.¹

Rate of Administration

Infuse slowly (i.e., >2 hours) to decrease the risk of adverse effects (e.g., infusion site reactions, renal impairment).^{6 17} (See Renal Effects under Cautions.)

For treatment of hypercalcemia associated with malignancy, infuse over at least 2–24 hours.¹

For treatment of Paget’s disease of bone, infuse over a 4-hour period once daily for 3 consecutive days.¹

For treatment of osteolytic bone metastases, infuse over a 2-hour period once every 3–4 weeks.¹

For treatment of osteolytic lesions of multiple myeloma, infuse over a 4-hour period once monthly.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage of pamidronate disodium is expressed in terms of the salt.¹

Adults

Hypercalcemia Associated with Malignancy

Moderate Hypercalcemia

IV

60–90 mg as a single dose over at least 2–24 hours in those with albumin-corrected serum calcium concentration approximately 12–13.5 mg/dL.¹

Consider retreatment if serum calcium concentrations do not return to normal or remain normal.¹ Repeat the dose appropriate for the degree of hypercalcemia no sooner than 7 days after the initial dose in order to allow full response to the initial dose.¹

Severe Hypercalcemia

IV

90-mg as a single dose over 2–24 hours in those with albumin-corrected serum calcium concentration >13.5 mg/dL.¹

Consider retreatment if serum calcium concentrations do not return to normal or remain normal.¹ Repeat the dose appropriate for the degree of hypercalcemia no sooner than 7 days after the initial dose in order to allow full response to the initial dose.¹

Paget’s Disease of Bone

IV

Initially, 30 mg, administered as a 4-hour infusion, once daily on 3 consecutive days (total cumulative dose 90 mg for the course).¹

Individualize the need for retreatment and base on patient response (e.g., increased serum alkaline phosphatase concentrations and urinary hydroxyproline).¹¹ When clinically indicated, retreat with the same dosage that was required for initial treatment.¹

Osteolytic Bone Metastases of Breast Cancer

IV

Initially, 90 mg, administered as a 2-hour infusion, given once every 3–4 weeks.¹ Optimum duration of such therapy is not known, but has been used at these intervals for 24 months.¹

Osteolytic Bone Lesions of Multiple Myeloma

IV

Initially, 90 mg, administered as a 4-hour infusion, given once monthly.¹ Optimum duration of therapy currently is not known, but monthly doses have been administered for 21 months.¹

Prescribing Limits

Adults

IV

Maximum 90 mg as a single dose.¹ Duration of IV infusion should be no less than 2 hours.¹

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment; not studied in patients with severe hepatic impairment.¹

Renal Impairment

Withhold therapy in patients with bone metastases associated with solid tumors or with osteolytic lesions associated wtih multiple myeloma if renal function deteriorates (defined as an increase in serum creatinine concentration of at least 0.5 or 1 mg/dL in patients with normal [<1.4 mg/dL] or elevated [≥1.4 mg/dL] baseline serum creatinine concentrations, respectively) during therapy until serum creatinine concentrations return to within 10% of baseline levels.¹

Cautions for Aredia

Contraindications

• 
  

  Known hypersensitivity to pamidronate or other bisphosphonates.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity

May cause fetal harm; use not recommended in pregnant women, and women of childbearing potential should avoid conception during therapy.¹ If patient becomes pregnant, apprise of potential fetal hazard.¹

Renal Effects

Possible renal toxicity (e.g., deterioration of renal function and potential renal failure).¹ Risk may be greater in patients with impaired renal function.¹ Monitor standard laboratory and clinical parameters of renal function (including serum creatinine) prior to each treatment.¹

May reduce the risk for renal toxicity by using the recommended duration of infusion (i.e., >2 hours), particularly in patients with preexisting renal insufficiency.¹

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Metabolic Effects

Asymptomatic hypophosphatemia,^{1 3 30 31 33} hypokalemia,¹ hypomagnesemia,^{1 33 38} and hypocalcemia reported.^{1 3 9 11 30 33} Rarely, symptomatic hypocalcemia, including tetany reported.¹

Carefully monitor standard hypercalcemia-related metabolic parameters (e.g., serum concentrations of calcium, phosphate, magnesium, and potassium) following initiation of therapy.¹ Institute short-term calcium and/or vitamin D therapy if hypocalcemia occurs.^{1 17 19}

Patients should be adequately hydrated throughout treatment of hypercalcemia of malignancy.¹ Avoid overhydration, especially in patients at risk for the development of cardiac failure.¹ Attempt to restore urine output to 2L/day throughout treatment.¹

Musculoskeletal Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Osteonecrosis and osteomyelitis of the jaws have been reported in cancer patients receiving bisphosphonates.^{1 41 42 43 44 45} Most patients were receiving concurrent chemotherapy and corticosteroids,¹ and the majority of cases were associated with dental procedures (e.g., tooth extraction).^{41 42 43 44 45}

A dental examination with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).^{1 41 42 43} Such patients should avoid invasive dental procedures if possible during therapy.^{1 42 43}

In the treatment of Paget’s disease of bone, monitor patients periodically (e.g., serum alkaline phosphatase concentrations and urinary hydroxyproline) for recurrence of disease.^{7 8 9 13 17 25 40}

Hematologic Effects

Anemia, leukopenia, neutropenia, and thrombocytopenia reported.¹ Monitor complete blood counts with differential and hematocrit and hemoglobin.¹ Carefully monitor patients with preexisting anemia, leukopenia, or thrombocytopenia in the first 2 weeks of treatment initiation.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Not known if pamidronate is distributed into milk.¹ Use with caution in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2}

Renal Impairment

Not studied in patients with severe renal impairment (serum creatinine concentration >5 mg/dL).¹ Not recommended for use in patients with severe renal impairment and bone metastases.¹ Carefully weigh the possible benefits and risks of therapy in other patients with severe renal impairment.¹ (See Renal Effects under Cautions.)

Common Adverse Effects

Hypercalcemia of malignancy: Infusion-site reactions (e.g., erythema, edema, induration, pain on palpation, thrombophlebitis), transient low-grade fever, hypokalemia, hypophosphatemia.^{1 3 9 10 16 20 22 30 33}

Paget’s disease of bone: Arthrosis, bone pain, hypertension, headache.¹

Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Fatigue, dyspnea, anorexia, dyspepsia, abdominal pain, anemia, myalgia, headache, coughing.¹

Interactions for Aredia

Nephrotoxic Agents

Potential for increased risk of nephrotoxicity.¹ Use concomitantly with caution.¹

Specific Drugs

Drug	Interaction	Comments
Diuretics, loop	No effect on calcium-lowering effect of pamidronate1

Aredia Pharmacokinetics

Absorption

Onset

Hypercalcemia associated with malignancy: Reduction of serum calcium concentration usually is apparent within 1–3 days^{1 3 4 33 38} and generally is maximal within 5–7 days.^{3 4 38}

Paget’s disease of bone: Onset of therapeutic response usually is evident within the first week.^{1 17} Symptomatic relief of bone pain usually is evident within 0.5–3 months after therapy.^{8 13 40} The median time to appreciable therapeutic response (≥50% decrease from baseline) for serum alkaline phosphatase was approximately 1 month.¹ Plateau at 5–12 months after therapy.^{7 8 9 13 17 25 40}

Bone metastases of breast cancer: Decrease in bone pain usually is evident within 2 weeks.^{1 20}

Duration

Hypercalcemia associated with malignancy: Normocalcemia persists about 6–14 days following a single dose.^{1 3 30 33 38}

Paget’s disease of bone: Reduction in marker of bone formation (decrease of serum alkaline phosphatase concentrations) persist from 1–372 day(s).^{1 9 11 13 14 15 16 40}

Special Populations

In patients with hepatic impairment, increased mean AUC and peak plasma concentrations.¹

Distribution

Extent

Distributed mainly to bones, liver, spleen, teeth, and tracheal cartilage in rats.¹ Protracted binding of the drug to the bone mineral matrix.^{1 4 15 20 22 26}

Pamidronate crosses the placenta in rats; not known whether distributed into human milk.¹

Elimination

Metabolism

No evidence of metabolism.^{1 4 15 20 22 26}

Elimination Route

Urinary excretion is the sole means of elimination.¹

Half-life

Averages 28 hours.¹ Rate of elimination from bone not determined.¹

Special Populations

In cancer patients with renal impairment, decreased clearance compared with cancer patients without renal impairment.¹ Accumulation of pamidronate is not anticipated when recommended dose is repeated on a monthly basis.¹

In patients with hepatic impairment, decreased plasma clearance.¹ Not thought to be clinically relevant.¹

Stability

Storage

Parenteral

Powder for Injection

≤30°C.¹

Store reconstituted solution at 2–8°C for up to 24 hours.¹

ActionsActions

• 
  

  Incorporates into bone and selectively inhibits osteoclast-mediated bone resorption.^{19 40}

  
  


• 
  

  Reduces biochemical markers of bone resorption, urinary calcium excretion, and urinary hydroxyproline in patients with breast cancer.^{10 20 28}

  
  


• 
  

  Hypocalcemic effect appears to result principally from inhibition of bone resorption and does not depend on cytotoxic activity or enhancement of renal calcium excretion.^{1 5 10 33 38}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise women to avoid pregnancy during therapy.¹ If patient becomes pregnant, apprise of potential fetal hazard.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pamidronate Disodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	30 mg	Aredia (with mannitol)	Novartis
		90 mg	Aredia (with mannitol)	Novartis

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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2. Ciba, Summit, NJ: Personal communication.

3. Gucalp R, Ritch P, Wiernik PH et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol. 1992; 10:134-42. [PubMed 1727915]

4. Thiébaud, Jaeger P, Jacquet AF et al. Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP. J Clin Oncol. 1988; 6:762-8. [PubMed 3367184]

5. Bilezikian JP. Management of acute hypercalcemia. N Engl J Med. 1992; 326:1196-203. [IDIS 295128] [PubMed 1532633]

6. Hosking DJ. Advances in the management of Paget’s disease of bone. Drugs. 1990; 40:829-40. [PubMed 2078998]

7. Cantrill JA, Buckler HM, Anderson DC. Low dose intravenous 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) for the treatment of Paget’s disease of bone. Ann Rheum Dis. 1986; 45:1012-8. [IDIS 224896] [PubMed 3813665]

8. Thiébaud D, Jaeger P, Gobelet C et al. A single infusion of the bisphosphonate AHPrBP (APD) as treatment of Paget’s disease of bone. Am J Med. 1988; 85:207-12. [IDIS 245310] [PubMed 3261129]

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24. Theriault R, Lipton A, Leff R et al. Reduction of skeletal related complications in breast cancer patients with osteolytic bone metastases receiving hormone therapy, by monthly pamidronate sodium (Aredia) infusion. Proc Am Soc Clin Oncol. 1996; 15:122.

25. Michalsky M, Stepan JJ, Wilczek H et al. Galactosyl hydroxylysine in assessment of Paget’s bone disease. Clin Chim Acta. 1995; 234:101-8. [PubMed 7758208]

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27. Hortobagyi GN, Porter L Blayney D et al. Reduction of skeletal related complications in breast cancer patients with osteolytic bone metastases receiving chemotherapy (CT), by monthly pamidronate sodium (PAM) (Aredia) infusion. Proc Am Soc Clin Oncol. 1996; 15:108.

28. Burckhardt P, Thiébaud D, Perey L et al. Treatment of tumor-induced osteolysis by APD. Recent Results Cancer Res. 1989; 116:54-66. [PubMed 2762665]

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34. Reid IR, Cundy T, Ibbertson HK et al. Osteomalacia after pamidronate for Paget’s disease. Lancet. 1994; 343:855. [IDIS 327910] [PubMed 7908098]

35. Ghose K, Waterworth R, Trolove P et al. Uveitis associated with pamidronate. Aust N Z J Med. 1994; 24:320. [PubMed 7980223]

36. Ignoffo RJ, Tseng A. Focus on pamidronate: a biphosphonate compound for the treatment of hypercalcemia of malignancy. Hosp Formul. 1991; 26:774,776-7,781,784-86.

37. Thürlimann B, Waldburger R, Senn HJ et al. Mithramycin and pamidronate (APD) in symptomatic tumour-related hypercalcaemia—a comparative randomised crossover trial. In: Bijvoet OLM, Lipton A eds. Osteoclast inhibition in the management of malignancy-related bone disorders: an international symposium held during the 15th International Cancer Congress, Hamburg, Germany, August 1990. Lewiston, NY: Hogrefe & Huber Publishers; 1991:27-32.

38. Morton A, Dodwell DJ, Howell A. Disodium pamidronate (APD) for the management of hypercalcaemia of malignancy: comparative studies of single-dose versus daily infusions and of infusion duration. In: Burckhardt P, ed. Disodium pamidronate (APD) in the treatment of malignancy-related disorders: an international symposium held during the 13th Congress of the European Society for Medical Oncology (ESMO), Lugano, Switzerland, October 1988. Toronto: Hans Huber Publishers; 1989:85-100.

39. Potts JT Jr. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Wilson JD, Braunwald E, Isselbacher KJ et al, eds. Harrison’s principles of internal medicine. 12th ed. New York: McGraw-Hill Book Co; 1991:1902-21.

40. Harinck HIJ, Bijvoet OLM, Blanksma HJ et al. Efficacious management with aminobisphosphonate (APD) in Paget’s disease of bone. Clin Orthop Relat Res. 1987; 217:79-98. [PubMed 2951049]

41. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofacial Surg. 2004; 62:527-34.

42. Novartis. Zometa(zoledronic acid) injection prescribing information. East Hanover, NJ; 2004 Aug.

43. Hohneker JA. Dear doctor letter regarding osteonecrosis of the jaw in patients with cancer receiving bisphophonates. East Hanover, NJ: Novartis; 2004 September 24.

44. Ruggiero SL, Mehrotra B. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004; 351:191.

45. Bone HG, Santora AC. Ten years of alendronate treatment for osteoporosis in postmenopausal women. N Engl J Med. 2004; 351:191-2.

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Zaroxolyn

Generic Name: metolazone

Dosage Form: Tablets, USP

DO NOT INTERCHANGE:

DO NOT INTERCHANGE Zaroxolyn TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY AND ARE NOT THERAPEUTICALLY EQUIVALENT AT THE SAME DOSES TO MYKROX® TABLETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY BIOAVAILABLE METOLAZONE PRODUCT. FORMULATIONS BIOEQUIVALENT TO Zaroxolyn AND FORMULATIONS BIOEQUIVALENT TO MYKROX SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.

Zaroxolyn Description

Zaroxolyn Tablets (metolazone tablets, USP) for oral administration contain 2½, 5, or 10 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.

Metolazone has the molecular formula C16H16ClN3S, the chemical name 7-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and a molecular weight of 365.83. The structural formula is:

Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents.

Inactive Ingredients: Magnesium stearate, microcrystalline cellulose and dye: 2½ mg-D&C Red No. 33; 5 mg-FD&C Blue No. 2; 10 mg-D&C Yellow No. 10 and FD&C Yellow No. 6.

Zaroxolyn - Clinical Pharmacology

Zaroxolyn (metolazone) is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of Zaroxolyn result from interference with the renal tubular mechanism of electrolyte reabsorption. Zaroxolyn acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Zaroxolyn does not inhibit carbonic anhydrase. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies.

When Zaroxolyn Tablets are given, diuresis and saluresis usually begin within one hour and may persist for 24 hours or more. For most patients, the duration of effect can be varied by adjusting the daily dose. High doses may prolong the effect. A single daily dose is recommended. When a desired therapeutic effect has been obtained, it may be possible to reduce dosage to a lower maintenance level.

The diuretic potency of Zaroxolyn at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, Zaroxolyn may produce diuresis in patients with glomerular filtration rates below 20 mL/min.

Zaroxolyn and furosemide administered concurrently have produced marked diuresis in some patients where edema or ascites was refractory to treatment with maximum recommended doses of these or other diuretics administered alone. The mechanism of this interaction is unknown (see WARNINGS and PRECAUTIONS, Drug Interactions).

Maximum blood levels of metolazone are found approximately eight hours after dosing. A small fraction of metolazone is metabolized. Most of the drug is excreted in the unconverted form in the urine.

Indications and Usage for Zaroxolyn

Zaroxolyn is indicated for the treatment of salt and water retention including:

• edema accompanying congestive heart failure;


• edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.

Zaroxolyn is also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. MYKROX Tablets, a more rapidly available form of metolazone, are intended for the treatment of new patients with mild to moderate hypertension. A dose titration is necessary if MYKROX Tablets are to be substituted for Zaroxolyn in the treatment of hypertension. See package circular for MYKROX Tablets (UCB).

Usage In Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Zaroxolyn is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (see PRECAUTIONS). Dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may be appropriate.

Contraindications

Anuria, hepatic coma or precoma, known allergy or hypersensitivity to metolazone.

Warnings

Rapid Onset Hyponatremia And/Or Hypokalemia

Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, drug should be discontinued and supportive measures should be initiated immediately. Parenteral electrolytes may be required. Appropriateness of therapy with this class of drugs should be carefully reevaluated.

Hypokalemia

Hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias. Serum potassium should be determined at regular and appropriate intervals, and dose reduction, potassium supplementation or addition of a potassium-sparing diuretic instituted whenever indicated. Hypokalemia is a particular hazard in patients who are digitalized or who have or have had a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Hypokalemia is dose related.

Concomitant Therapy

Lithium

In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

Furosemide

Unusually large or prolonged losses of fluids and electrolytes may result when Zaroxolyn is administered concomitantly to patients receiving furosemide (see PRECAUTIONS, Drug Interactions).

Other Antihypertensive Drugs

When Zaroxolyn is used with other antihypertensive drugs, particular care must be taken to avoid excessive reduction of blood pressure, especially during initial therapy.

Cross-Allergy

Cross-allergy may occur when Zaroxolyn is given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.

Sensitivity Reactions

Sensitivity reactions (e.g., angioedema, bronchospasm) may occur with or without a history of allergy or bronchial asthma and may occur with the first dose of Zaroxolyn.

Precautions

DO NOT INTERCHANGE :

DO NOT INTERCHANGE Zaroxolyn TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY AND ARE NOT THERAPEUTICALLY EQUIVALENT AT THE SAME DOSES TO MYKROX TABLETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY BIOAVAILABLE METOLAZONE PRODUCT. FORMULATIONS BIOEQUIVALENT TO Zaroxolyn AND FORMULATIONS BIOEQUIVALENT TO MYKROX SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.

General

Fluid And Electrolytes

All patients receiving therapy with Zaroxolyn Tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening.

The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.

Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Glucose Tolerance

Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.

Hyperuricemia

Zaroxolyn regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.

Azotemia

Azotemia, presumably prerenal azotemia, may be precipitated during the administration of Zaroxolyn. If azotemia and oliguria worsen during treatment of patients with severe renal disease, Zaroxolyn should be discontinued.

Renal Impairment

Use caution when administering Zaroxolyn Tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.

Orthostatic Hypotension

Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.

Hypercalcemia

Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.

Systemic Lupus Erythematosus

Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with Zaroxolyn Tablets.

Information For Patients

Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.

Drug Interactions

Diuretics

Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes (see WARNINGS).

Other Antihypertensives

When Zaroxolyn Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.

Alcohol, Barbiturates, And Narcotics

The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.

Digitalis Glycosides

Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.

Corticosteroids Or ACTH

May increase the risk of hypokalemia and increase salt and water retention.

Lithium

Serum lithium levels may increase (see WARNINGS).

Curariform Drugs

Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue Zaroxolyn three days before elective surgery.

Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs

May decrease the antihypertensive effects of Zaroxolyn Tablets.

Sympathomimetics

Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Insulin And Oral Antidiabetic Agents

See Glucose Tolerance under PRECAUTIONS, General.

Methenamine

Efficacy may be decreased due to urinary alkalizing effect of metolazone.

Anticoagulants

Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.

Drug/Laboratory Test Interactions

None reported.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies.

Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.

Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zaroxolyn Tablets (metolazone tablets, USP) should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.

Non-Teratogenic Effects

The use of Zaroxolyn Tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.

Labor And Delivery

Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.

Nursing Mothers

Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established in controlled clinical trials. There is limited experience with the use of Zaroxolyn in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.

There is limited experience with the combination of Zaroxolyn and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after Zaroxolyn was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated. See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS.

Geriatric Use

Clinical studies of Zaroxolyn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Zaroxolyn is usually well tolerated, and most reported adverse reactions have been mild and transient. Many Zaroxolyn related adverse reactions represent extensions of its expected pharmacologic activity and can be attributed to either its antihypertensive action or its renal/metabolic actions. The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.

Cardiovascular

Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.

Central And Peripheral Nervous System

Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness (sometimes resulting in insomnia), headache.

Dermatologic/Hypersensitivity

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome, necrotizing angiitis (cutaneous vasculitis), skin necrosis, purpura, petechiae, dermatitis (photosensitivity), urticaria, pruritus, skin rashes.

Gastrointestinal

Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating, abdominal pain.

Hematologic

Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Metabolic

Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia.

Musculoskeletal

Joint pain, acute gouty attacks, muscle cramps or spasm.

Other

Transient blurred vision, chills, dry mouth.

In addition, adverse reactions reported with similar antihypertensive-diuretics, but which have not been reported to date for Zaroxolyn include: bitter taste, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of Zaroxolyn.

Whenever adverse reactions are moderate or severe, Zaroxolyn dosage should be reduced or therapy withdrawn.

Overdosage

Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.

Signs And Symptoms

Orthostatic hypotension, dizziness, drowsiness, syncope, electrolyte abnormalities, hemoconcentration and hemodynamic changes due to plasma volume depletion may occur. In some instances depressed respiration may be observed. At high doses, lethargy of varying degree may progress to coma within a few hours. The mechanism of CNS depression with thiazide overdosage is unknown. Also, GI irritation and hypermotility may occur. Temporary elevation of BUN has been reported, especially in patients with impairment of renal function. Serum electrolyte changes and cardiovascular and renal function should be closely monitored.

Treatment

There is no specific antidote available but immediate evacuation of stomach contents is advised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastric contents to prevent aspiration, especially in the stuporous or comatose patient. Supportive measures should be initiated as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.

Zaroxolyn Dosage and Administration

Effective dosage of Zaroxolyn should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with Zaroxolyn should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.

Usual Single Daily Dosage Schedules

Suitable initial dosages will usually fall in the ranges given.

Edema of cardiac failure:

   Zaroxolyn 5 to 20 mg once daily.

Edema of renal disease:

   Zaroxolyn 5 to 20 mg once daily.

Mild to moderate essential hypertension:

   Zaroxolyn 2½ to 5 mg once daily.

New patients – MYKROX Tablets (metolazone tablets, USP) (see MYKROX package circular). If considered desirable to switch patients currently on Zaroxolyn to MYKROX, the dose should be determined by titration starting at one tablet (1/2 mg) once daily and increasing to two tablets (1 mg) once daily if needed.

Treatment Of Edematous States

The time interval required for the initial dosage to produce an effect may vary. Diuresis and saluresis usually begin within one hour and persist for 24 hours or longer. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible. The daily dose depends on the severity of the patient’s condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive drugs or diuretics are given concurrently with Zaroxolyn, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnal dyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.

Treatment Of Hypertension

The time interval required for the initial dosage regimen to show effect may vary from three or four days to three to six weeks in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.

How is Zaroxolyn Supplied

Zaroxolyn Tablets (metolazone tablets, USP) are shallow biconvex, round tablets, and are available in three strengths:

2½ mg, pink, debossed “Zaroxolyn” on one side, and “2½” on reverse side.

   NDC 53014-975-71 Bottle of 100’s

5 mg, blue, debossed “Zaroxolyn” on one side, and “5” on reverse side.

   NDC 53014-850-71 Bottle of 100’s

10 mg, yellow, debossed “Zaroxolyn” on one side, and “10” on reverse side.

   NDC 53014-835-71 Bottle of 100’s

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. Keep out of the reach of children.

For Medical Information

Contact: Medical Affairs Department

Phone: (866) 822-0068

Fax: (770) 970-8859

UCB, Inc.

Smyrna, GA 30080

Zaroxolyn is a registered trademark of UCB Manufacturing, Inc., Rochester, NY 14623

© 2007, UCB, Inc., Smyrna, GA 30080

All rights reserved.

Rev. 1E 06/2007

4000671

Zaroxolyn  metolazone  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 53014-835 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength metolazone (metolazone) Active 10 MILLIGRAM  In 1 TABLET magnesium stearate Inactive   microcrystalline cellulose Inactive   D & C Yellow No. 10 Inactive   FD & C Yellow No. 6 Inactive

Product Characteristics Color YELLOW (YELLOW) Score no score Shape ROUND (ROUND) Size 6mm Flavor Imprint Code Zaroxolyn;10 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 53014-835-71 100 TABLET In 1 BOTTLE, PLASTIC None

Zaroxolyn  metolazone  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 53014-975 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength metolazone (metolazone) Active 2.5 MILLIGRAM  In 1 TABLET magnesium stearate Inactive   microcrystalline cellulose Inactive   D & C Red No. 33 Inactive

Product Characteristics Color PINK (PINK) Score no score Shape ROUND (ROUND) Size 6mm Flavor Imprint Code Zaroxolyn;2;1/2 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 53014-975-71 100 TABLET In 1 BOTTLE, PLASTIC None

Zaroxolyn  metolazone  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 53014-850 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength metolazone (metolazone) Active 5 MILLIGRAM  In 1 TABLET magnesium stearate Inactive   microcrystalline cellulose Inactive   FD & C Blue No. 2 Inactive

Product Characteristics Color BLUE (BLUE) Score no score Shape ROUND (ROUND) Size 6mm Flavor Imprint Code Zaroxolyn;5 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 53014-850-71 100 TABLET In 1 BOTTLE, PLASTIC None

Revised: 01/2008UCB, Inc.

More Zaroxolyn resources

• Zaroxolyn Side Effects (in more detail)
• Zaroxolyn Dosage
• Zaroxolyn Use in Pregnancy & Breastfeeding
• Drug Images
• Zaroxolyn Drug Interactions
• Zaroxolyn Support Group
• 1 Review for Zaroxolyn - Add your own review/rating

• Zaroxolyn Concise Consumer Information (Cerner Multum)


• Zaroxolyn MedFacts Consumer Leaflet (Wolters Kluwer)


• Zaroxolyn Monograph (AHFS DI)


• Zaroxolyn Advanced Consumer (Micromedex) - Includes Dosage Information


• Metolazone Professional Patient Advice (Wolters Kluwer)

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• Edema
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Aminosyn 10%

Dosage Form: injection, solution
Aminosyn® 10% (pH 6)

Sulfite-Free

AN AMINO ACID INJECTION

Flexible Plastic Container

Rx only

Aminosyn 10% Description

Aminosyn® 10% (pH 6), Sulfite-Free, (an amino acid injection) is a sterile, nonpyrogenic solution for intravenous infusion. Aminosyn 10% (pH 6) is oxygen sensitive.

Essential Amino Acids (mg/100 mL)

Aminosyn (pH 6)	10%
Isoleucine	720
Leucine	940
Lysine (acetate)*	720
Methionine	400
Phenylalanine	440
Threonine	520
Tryptophan	160
Valine	800
*Amount cited is for L-lysine alone and does not include the acetate salt.

Nonessential Amino Acids (mg/100 mL)

Aminosyn (pH 6)	10%
Alanine	1280
Arginine	980
Histidine	300
Proline	860
Serine	420
Tyrosine	44
Glycine	1280

Electrolytes (mEq/Liter)

Aminosyn (pH 6)	10%
Potassium (K+)	None
Chloride (Cl-)	None
Acetate (C2H3O2-)b	111a
a Includes acetate from acetic acid used in processing and from L-lysine acetate. b Adjusted with acetic acid.

Product Characteristics

Aminosyn (pH 6)	10%
Protein Equivalent     (approx. grams/liter)	100
Total Nitrogen     (grams/liter)	15.7
Osmolarity     (mOsmol/liter)	938
pH	6.0 (5.5 − 6.5)b
b Adjusted with acetic acid.

The formulas for the individual amino acids present in Aminosyn 10% (pH 6) are as follows:

Essential Amino Acids

Isoleucine, USP	C6H13NO2
Leucine, USP	C6H13NO2
Lysine Acetate, USP	C6H14N2O2 • CH3COOH
Methionine, USP	C5H11NO2S
Phenylalanine, USP	C9H11NO2
Threonine, USP	C4H9NO3
Tryptophan, USP	C11H12N2O2
Valine, USP	C5H11NO2

Nonessential Amino Acids

Alanine, USP	C3H7NO2
Arginine, USP	C6H14N4O2
Histidine, USP	C6H9N3O2
Proline, USP	C5H9NO2
Serine, USP	C3H7NO3
Tyrosine, USP	C9H11NO3
Glycine, USP	C2H5NO2

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.

Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

Aminosyn 10% - Clinical Pharmacology

Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection) provides amino acids to promote protein synthesis and wound healing, and to reduce the rate of endogenous protein catabolism. Aminosyn 10% (pH 6), given by central venous infusion in combination with concentrated dextrose, electrolytes, vitamins, trace metals, and ancillary fat supplements, constitutes total parenteral nutrition (TPN). Aminosyn 10% (pH 6) can also be administered by peripheral vein with dextrose and maintenance electrolytes. Intravenous fat emulsion may be substituted for part of the carbohydrate calories during either TPN or peripheral vein administration of Aminosyn 10% (pH 6).

Indications and Usage for Aminosyn 10%

Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection) infused with dextrose by peripheral vein infusion is indicated as a source of nitrogen in the nutritional support of patients with adequate stores of body fat, in whom, for short periods of time, oral nutrition cannot be tolerated, is undesirable, or inadequate.

SUPPLEMENTAL ELECTROLYTES, IN ACCORDANCE WITH THE PRESCRIPTION OF THE ATTENDING PHYSICIAN, MUST BE ADDED TO AMINOSYN SOLUTIONS WITHOUT ELECTROLYTES.

Aminosyn 10% (pH 6) can be administered peripherally with dilute (5% to 10%) dextrose solution and I.V. fat emulsion as a source of nutritional support in patients who, while not hypermetabolic, cannot be satisfactorily maintained on peripheral intravenous nutrition. This form of nutritional support can help to preserve protein and reduce catabolism in stress conditions where oral intake is inadequate.

When administered with concentrated dextrose solutions with or without fat emulsions, Aminosyn 10% (pH 6) is also indicated for central vein infusion to prevent or reverse negative nitrogen balance in patients where: (a) the alimentary tract, by the oral, gastrostomy or jejunostomy route cannot or should not be used; (b) gastrointestinal absorption of protein is impaired; (c) metabolic requirements for protein are substantially increased as with extensive burns and (d) morbidity and mortality may be reduced by replacing amino acids lost from tissue breakdown, thereby preserving tissue reserves, as in acute renal failure.

Contraindications

This preparation should not be used in patients with hepatic coma or metabolic disorders involving impaired nitrogen utilization.

Warnings

Intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN), especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limits and continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake.

Administration of amino acid solutions to a patient with hepatic insufficiency may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.

Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component.

Solutions containing sodium ion should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.

Solutions which contain potassium ion should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.

Solutions containing acetate ion should be used with great care in patients with metabolic or respiratory alkalosis. Acetate should be administered with great care in those conditions in which there is an increased level or an impaired utilization of this ion, such as severe hepatic insufficiency.

Hyperammonemia is of special significance in infants, as it can result in mental retardation. Therefore, it is essential that blood ammonia levels be measured frequently in infants.

Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. The mechanisms of this reaction are not clearly defined, but may involve genetic defects and immature or subclinically impaired liver function.

Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection) can be infused simultaneously with fat emulsion by means of a Y-connector located near the infusion site using separate flow rate controls for each solution.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Precautions

Special care must be taken when administering glucose to provide calories in diabetic or prediabetic patients.

Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur.

Intravenous feeding regimens which include amino acids should be used with caution in patients with history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.

The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.

Nitrogen intake should be carefully monitored in patients with impaired renal function. For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.

SPECIAL PRECAUTIONS FOR CENTRAL VENOUS INFUSIONS ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.

 

Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL BASED ON CURRENT MEDICAL PRACTICES BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

SUMMARY HIGHLIGHTS OF COMPLICATIONS (consult current medical literature.)

1. Technical

The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.

2. Septic

The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.

Solutions should ideally be prepared in the hospital pharmacy in a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.

Administration time for a single container and set should never exceed 24 hours.

3. Metabolic

The following metabolic complications have been reported with TPN administration: metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, glycosuria, hyperglycemia, hyperosmolar nonketotic states and dehydration, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.

Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death.

Pregnancy Category C

Animal reproduction studies have not been conducted with Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection). It is not known whether Aminosyn 10% (pH 6) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn 10% (pH 6) should be given to a pregnant woman only if clearly needed.

Geriatric Use

Clinical studies of Aminosyn 10% (pH 6) have not been performed to determine whether patients over 65 years respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal functions.

CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN, ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.

Aminosyn 10% (pH 6) contains no more than 25 mcg/L of aluminum.

Drug Interactions

Because of its antianabolic activity, concurrent administration of tetracycline may reduce the potential anabolic effects of amino acids infused with dextrose as part of a parenteral feeding regimen.

Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

Adverse Reactions

Peripheral Infusions

Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection) is hypertonic and must be diluted prior to administration by peripheral vein. Local reactions consisting of a warm sensation, erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids particularly if other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Simultaneous administration of Aminosyn/dextrose admixtures with intravenous lipid emulsion may reduce the likelihood of peripheral vein irritation. Electrolyte additives should be spread throughout the day. Irritating additive medications may need to be injected at another venous site.

Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.

Overdosage

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.

Aminosyn 10% Dosage and Administration

The total daily dose of the solution depends on the daily protein requirements and on the patient’s metabolic and clinical response. In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose infusions are abruptly discontinued.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COLOR VARIATION FROM PALE YELLOW TO YELLOW IS NORMAL AND DOES NOT ALTER EFFICACY.

1. Peripheral Vein Nutritional Maintenance

Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection) may be diluted with 5% to 10% Dextrose Injection to achieve a final amino acid concentration of 3.5, 4.25 or 5% for peripheral administration.

For peripheral intravenous infusion, 1.0 to 1.5 g/kg/day of total amino acids will achieve optimal fat mobilization and reduce protein catabolism. Infusion or ingestion of carbohydrate or lipid will not reduce the nitrogen sparing effect of intravenous amino acid infusions at this dose.

As with all intravenous fluid therapy, the primary aim is to provide sufficient water to compensate for insensible, urinary and other (nasogastric suction, fistula drainage, diarrhea) fluid losses. Total fluid requirements, as well as electrolyte and acid-base needs, should be estimated and appropriately administered.

For an amino acid solution of specified total concentration, the volume required to meet amino acid requirements per 24 hours can be calculated. After making an estimate of the total daily fluid (water) requirement, the balance of fluid needed beyond the volume of amino acid solution required can be provided either as a noncarbohydrate or a carbohydrate-containing electrolyte solution. I.V. lipid emulsion may be substituted for part of the carbohydrate containing solution. Vitamins and additional electrolytes as needed for maintenance or to correct imbalances may be added to the amino acid solution.

If desired, only one-half of an estimated daily amino acid requirement of 1.5 g/kg can be given on the first day. Amino acids together with dextrose in concentrations of 5% to 10%, infused into a peripheral vein can be continued while oral nutrition is impaired. However, if a patient is unable to take oral nourishment for a prolonged period of time, institution of total parenteral nutrition with exogenous calories should be considered.

2. Central Vein Total Parenteral Nutrition

For central vein infusion with concentrated dextrose solution, alone or with I.V. lipid, the total daily dose of the amino acid solution depends upon daily protein requirements and the patient’s metabolic and clinical response. The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements.

Adults

Diluted solutions containing 3.5 to 5% amino acids with 5 to 10% glucose may be coinfused with a fat emulsion by peripheral vein to provide approximately 1400 to 2000 kcal/day.

Aminosyn 10% (pH 6) solution should only be infused via a central vein when admixed with sufficient dextrose to provide full caloric requirements in patients who require prolonged total parenteral nutrition. I.V. lipid may be administered separately to provide part of the calories, if desired.

Total parenteral nutrition (TPN) may be started with 10% dextrose added to the calculated daily requirement of amino acids (1.5 g/kg for a metabolically stable patient). Dextrose content is gradually increased over the next few days to the estimated daily caloric need as the patient adapts to the increasing amounts of dextrose. Each gram of dextrose provides approximately 3.4 kcal. Each gram of fat provides 9 kcal.

The average depleted major surgical patient with complications requires between 2500 and 4000 kcal and between 12 and 24 grams of nitrogen per day. An adult patient in an acceptable weight range with restricted activity who is not hypermetabolic, requires about 30 kcal/kg of body weight/day. Average daily adult fluid requirements are between 2500 and 3000 mL and may be much higher with losses from fistula drainage or severe burns. Typically, a hospitalized patient may lose 12 to 18 grams of nitrogen a day, and in severe trauma the daily loss may be 20 to 25 grams or more.

Aminosyn solutions without electrolytes are intended for patients requiring individualized electrolyte therapy. Sodium, chloride, potassium, phosphate, calcium and magnesium are major electrolytes which should be added to Aminosyn as required.

SERUM ELECTROLYTES SHOULD BE MONITORED AS INDICATED. Electrolytes may be added to the nutrient solution as indicated by the patient’s clinical condition and laboratory determinations of plasma values. Major electrolytes are sodium, chloride, potassium, phosphate, magnesium and calcium. Vitamins, including folic acid and vitamin K are required additives. The trace element supplements should be given when long-term parenteral nutrition is undertaken.

Calcium and phosphorus are added to the solution as indicated. The usual dose of phosphate added to a liter of TPN solution (containing 25% dextrose) is 12mM. This requirement is related to the carbohydrate calories delivered. Iron is added to the solution or given intramuscularly in depot form as indicated. Vitamin B12, vitamin K and folic acid are given intramuscularly or added to the solution as desired.

Calcium and phosphate additives are potentially incompatible when added to the TPN admixture. However, if one additive is added to the amino acid container, and the other to the container of concentrated dextrose, and if the contents of both containers are swirled before they are combined, then the likelihood of physical incompatibility is reduced.

In patients with hyperchloremic or other metabolic acidosis, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate alternates.

In adults, hypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the vena cava. Typically, the 10% solution is used in equal volume with 50% dextrose to provide an admixture containing 5% amino acids and 25% dextrose.

The rate of intravenous infusion initially should be 2 mL/min and may be increased gradually. If administration should fall behind schedule, no attempt to “catch up” to planned intake should be made. In addition to meeting protein needs, the rate of administration is governed by the patient’s glucose tolerance estimated by glucose levels in blood and urine.

Aminosyn 10% (pH 6) solution, when mixed with an appropriate volume of concentrated dextrose, offers a higher concentration of calories and nitrogen per unit volume. This solution is indicated for patients requiring larger amounts of nitrogen than could otherwise be provided or where total fluid load must be kept to a minimum, for example, patients with renal failure.

Provision of adequate calories in the form of hypertonic dextrose may require exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, do not abruptly discontinue administration of nutritional solutions.

Pediatric

Pediatric requirements for parenteral nutrition are constrained by the greater relative fluid requirements of the infant and greater caloric requirements per kilogram. Amino acids are probably best administered in a 2.5% concentration. For most pediatric patients on intravenous nutrition, 2.5 grams amino acids/kg/day with dextrose alone or with I.V. lipid calories of 100 to 130 kcal/kg/day is recommended. In cases of malnutrition or stress, these requirements may be increased. It is acceptable in pediatrics to start with a nutritional solution of half strength at a rate of about 60 to 70 mL/kg/day. Within 24 to 48 hours the volume and concentration of the solution can be increased until the full strength pediatric solution (amino acids and dextrose) is given at a rate of 125 to 150 mL/kg/day.

Supplemental electrolytes and vitamin additives should be administered as deemed necessary by careful monitoring of blood chemistries and nutritional status. Addition of iron is more critical in the infant than the adult because of the increasing red cell mass required for the growing infant. Serum lipids should be monitored for evidence of essential fatty acid deficiency in patients maintained on fat-free TPN. Bicarbonate should not be administered during infusion of the nutritional solution unless deemed absolutely necessary.

To ensure the precise delivery of the small volumes of fluid necessary for total parenteral nutrition in infants, accurately calibrated and reliable infusion systems should be used.

A basic solution for pediatric use should contain 25 grams of amino acids and 200 to 250 grams of glucose per 1000 mL, administered from containers containing 500 mL or less. Such a solution given at the rate of 145 mL/kg/day provides 130 kcal/kg/day.

WARNING: Do not use flexible container in series connections.

How is Aminosyn 10% Supplied

NDC No.	Concentration	Container (mL)
0409-4192-05	Aminosyn 10% (pH 6), Sulfite-Free, (an amino acid injection)	1000

Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.] Protect from freezing. Avoid exposure to light until use.

Revised: June, 2008

Printed in USA                            EN - 1818

Hospira, Inc., Lake Forest, IL 60045 USA

IM-0298

AMINOSYN SULFITE FREE  isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, proline, serine, tyrosine, and glycine  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4192 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ISOLEUCINE (ISOLEUCINE) ISOLEUCINE 720 mg  in 100 mL LEUCINE (LEUCINE) LEUCINE 940 mg  in 100 mL LYSINE ACETATE (LYSINE) LYSINE 720 mg  in 100 mL METHIONINE (METHIONINE) METHIONINE 400 mg  in 100 mL PHENYLALANINE (PHENYLALANINE) PHENYLALANINE 440 mg  in 100 mL THREONINE (THREONINE) THREONINE 520 mg  in 100 mL TRYPTOPHAN (TRYPTOPHAN) TRYPTOPHAN 160 mg  in 100 mL VALINE (VALINE) VALINE 800 mg  in 100 mL ALANINE (ALANINE) ALANINE 1280 mg  in 100 mL ARGININE (ARGININE) ARGININE 980 mg  in 100 mL HISTIDINE (HISTIDINE) HISTIDINE 300 mg  in 100 mL PROLINE (PROLINE) PROLINE 860 mg  in 100 mL SERINE (SERINE) SERINE 420 mg  in 100 mL TYROSINE (TYROSINE) TYROSINE 44 mg  in 100 mL GLYCINE (GLYCINE) GLYCINE 1280 mg  in 100 mL

Inactive Ingredients Ingredient Name Strength ACETIC ACID

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4192-05 6 POUCH In 1 CASE contains a POUCH 1 1 BAG In 1 POUCH This package is contained within the CASE (0409-4192-05) and contains a BAG 1 1000 mL In 1 BAG This package is contained within a POUCH and a CASE (0409-4192-05)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA017673	10/27/2011

Labeler - Hospira, Inc. (141588017)

Revised: 10/2011Hospira, Inc.

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