Zoledronic Acid

Class: Bone Resorption Inhibitors
VA Class: HS900
Chemical Name: [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bis-phosphonic acid monohydrate
Molecular Formula: C₅H₁₀N₂O₇P₂•H₂O
CAS Number: 165800-06-6
Brands: Zometa

Special Alerts:

[Posted 09/01/2011] ISSUE: FDA notified healthcare professionals and patients of an update to the drug label for zoledronic acid (Reclast) regarding the risk of kidney failure. Cases of acute renal failure requiring dialysis or having a fatal outcome following Reclast use have been reported to FDA. The revised label states that Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment. The label also recommends that healthcare professionals screen patients prior to administering Reclast in order to identify at-risk patients.

The Reclast Medication Guide for patients is being updated to contain information about the risk of severe kidney problems. In addition, the manufacturer of Reclast will issue a Dear Healthcare Provider letter to inform healthcare professionals about this risk.

BACKGROUND: Risk factors for developing renal failure include underlying moderate to severe renal impairment, use of kidney-damaging (nephrotoxic) or diuretic medications at the same time as Reclast, or severe dehydration occurring before or after Reclast is given. The risk of developing renal failure in patients with underlying renal impairment also increases with age.

These labeling changes are being made to the Reclast label only, although zoledronic acid, also sold as Zometa, is approved for treatment of cancer-related indications. Renal toxicity is already addressed in the Warnings and Precautions section of the Zometa label. Dose reductions for Zometa are provided for patients with renal impairment.

RECOMMENDATIONS: Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min, or in patients with evidence of acute renal impairment. Healthcare professionals should screen patients prior to administering Reclast in order to identify at-risk patients. Healthcare professionals should also monitor renal function in patients who are receiving Reclast. For more information visit the FDA website at: and .

[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 .

[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 .

REMS:

FDA approved a REMS for zoledronic acid to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Zoledronic Acid

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 (albumin-corrected serum calcium concentration ≥12 mg/dL) associated with malignant neoplasms.^{1 2 3 5}

Retreatment may be considered in patients with recurrent or refractory disease.^{1 2 3}

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

Used as an adjunct to antineoplastic therapy for the treatment of osteolytic bone metastases of solid tumors and osteolytic lesions of multiple myeloma.^{1 7}

Second-line therapy of bone metastases associated with prostate cancer in patients with disease progression following one or more hormonal therapies.^{1 3}

Prevention of Aromatase Inhibitor-associated Bone Loss in Postmenopausal Women

May be considered a reasonable choice (accepted, with possible conditions) in postmenopausal women with early-stage breast cancer receiving aromatase inhibitor therapy† who have no additional risk factors and in whom BMD is at least 2.5 standard deviations below normal (T-scores at or below -2.5) either at baseline or during aromatase inhibitor therapy.^{27 10005}

May be considered a reasonable choice (accepted, with possible conditions) on an individualized basis in postmenopausal women with early-stage breast cancer receiving aromatase inhibitor therapy† who have moderate osteopenia (T-scores at or below -2) and have a history of a prior fracture or another clinically important risk factor (e.g., age, maternal history of fracture, low weight or body mass index) or lifestyle-related factor as defined by WHO; such women are at moderate to high risk for fracture development.²⁷

Prevention of Aromatase Inhibitor-associated Bone Loss in Premenopausal Women

Use not fully established because of unclear risk/benefit.²⁷ Improvements in BMD observed in premenopausal women with early-stage breast cancer receiving zoledronic acid concurrently with an aromatase inhibitor-gonadotropin-releasing hormone agonist regimen†.¹⁰⁰⁰⁴ However, long-term follow-up needed, especially as women enter menopause, to establish whether zoledronic acid is associated with clinically important fracture reduction.¹⁰⁰⁰⁴

Zoledronic Acid 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 hematocrit and hemoglobin regularly.¹

  
  


• 
  

  Evaluate S_cr prior to administration of each dose.^{1 3} (See Renal Effects under Cautions.)

  
  


• 
  

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

  
  

Hypercalcemia Associated with Malignancy

• 
  

  Adequately hydrate patients prior to treatment initiation and throughout treatment.^{1 3} Avoid overhydration, especially in patients at risk for the development of heart failure.^{1 3} Attempt to restore urine output to 2 L/day throughout treatment.¹

  
  

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

• 
  

  Supplemental calcium (500 mg of elemental calcium daily) and a multivitamin containing vitamin D (400 units daily) is recommended in patients with multiple myeloma or bone metastases associated with solid tumors.^{1 7} (See Metabolic Effects under Cautions.)

  
  

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.^{1 3 7}

Must be diluted prior to administration.¹

Dilution

Withdraw the appropriate volume of zoledronic acid concentrate needed to provide the prescribed dose (see Table 1) from the 5-mL vial and dilute in 100 mL of 0.9% sodium chloride or 5% dextrose injection.¹ Increased risk of renal impairment or failure associated with smaller infusion volumes (e.g., 50 mL).^{3 4 7}

To avoid inadvertent injection of the concentrated solution, do not store the undiluted concentrate in a syringe.¹

Table 1. Zoledronic Acid Dose and Corresponding Volume of Concentrate for Dilution

Zoledronic Acid Dose	Volume of Concentrate to be Diluted
4 mg	5 mL
3.5 mg	4.4. mL
3.3 mg	4.1 mL
3 mg	3.8 mL

Rate of Administration

Administer by IV infusion over ≥15 minutes.^{1 3 7} Rapid IV infusion rates (5 minutes) are associated with an increased risk of renal impairment and renal failure.^{1 3 4 7}

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.

Available as zoledronic acid (as the monohydrate); dosage expressed in terms of the anhydrous drug.^{1 1}

Adults

Hypercalcemia Associated with Malignancy

IV

4 mg as a single dose in patients with an albumin-corrected serum calcium concentration of ≥12 mg/dL.^{1 3}

Consider retreatment if serum calcium concentrations do not return to normal or do not remain normal.¹ Initial dose can be repeated ≥7 days after treatment initiation to allow full response to initial dose.¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

IV

4 mg once every 3–4 weeks in patients with baseline Cl_cr >60 mL/minute.^{1 3} Optimum duration of such therapy is not known, but has been used at the recommended interval for 4–12 months.^{1 3 7}

If renal function deteriorates (defined as an increase in S_cr of ≥0.5 mg/dL) in patients with a baseline S_cr of <1.4 mg/dL, withhold therapy until S_cr returns to within 10% of baseline levels.^{1 3 7} Reinitiate therapy at the same dosage used prior to treatment interruption.^{1 3 7}

Prevention of Aromatase Inhibitor-associated Bone Loss† in Postmenopausal Women

IV

Dosage of 4 mg once every 6 months has been used in clinical trials in women with early-stage breast cancer.¹⁰⁰⁰¹

Prescribing Limits

Adults

Hypercalcemia Associated with Malignancy

IV

Maximum 4 mg as a single dose.^{1 3 5 7} Safety and efficacy of >1 course of retreatment not established.^{2 3}

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

IV

Maximum 4 mg as a single dose.^{1 3 5 7}

Special Populations

Hepatic Impairment

No dosage recommendations at this time.¹

Renal Impairment

Hypercalcemia Associated with Malignancy

IV

Dosage adjustments are not necessary in patients with mild to moderate renal impairment (S_cr <4.5 mg/dL).¹

Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma

IV

In patients with mild to moderate renal impairment (baseline Cl_cr of 30–60 mL/minute), lower initial dosages of zoledronic acid are recommended.¹ (See Table 2.)

Table 2. Initial Dosage in Adults with Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma Based on Renal Function

Calculated Clcr (mL/minute)	IV Dosage
>60	4 mg every 3–4 weeks
50–60	3.5 mg every 3–4 weeks
40–49	3.3 mg every 3–4 weeks
30–39	3 mg every 3–4 weeks

If renal function deteriorates (defined as an increase in S_cr of ≥1 mg/dL) in patients with a baseline S_cr of ≥1.4 mg/dL, withhold therapy until S_cr returns to within 10% of baseline levels.^{1 3 7} Reinitiate therapy at the same dosage that was used prior to the treatment interruption.¹ Studies in this patient population included individuals with S_cr <3 mg/dL.^{1 3 7}

Geriatric Patients

No dosage recommendations at this time.¹

Cautions for Zoledronic Acid

Contraindications

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.

• 
  

  Known hypersensitivity to zoledronic acid, other bisphosphonates, or any ingredient in the formulation.^{1 2}

  
  

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 (See Advice to Patients.)

Renal 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.

Renal toxicity (e.g., deterioration of renal function and potential renal failure)^{1 2 3 4 7} has occurred following administration of higher than recommended doses.¹ Renal impairment also has occurred after administration of the usual dose (4 mg) infused over the recommended infusion period (15 minutes)^{1 11} and after administration of the usual initial dose.¹

Risk of adverse renal effects depends on coexisting conditions, concomitant nephrotoxic therapy, preexisting renal disease, dosage, infusion volume and rate, dehydration, and multiple cycles of treatment.^{1 2 3 4 5 7} Such risk factors should be identified and managed.¹ Weigh the risks versus the potential benefits of subsequent treatment in patients with hypercalcemia of malignancy and severe renal impairment if renal function deteriorates during therapy.¹

Monitor S_cr and assess possible deterioration in renal function prior to each dose.^{1 3}

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

Possible hypocalcemia, hypophosphatemia, or hypomagnesemia.¹

Carefully monitor standard hypercalcemia-related metabolic parameters (e.g., serum concentrations of calcium, phosphate, magnesium, and potassium) following initiation of therapy.^{1 3} Institute short-term supplemental therapy if hypocalcemia, hypophosphatemia, or hypomagnesemia occurs.^{1 3}

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 jaw have been reported in cancer patients receiving bisphosphonates.^{1 12 13 14} Most patients were receiving concurrent chemotherapy and corticosteroids^{1 13 14} and the majority of cases were associated with dental procedures (e.g., tooth extraction).^{1 12 13 14}

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 12 13} Avoid invasive dental procedures if possible during therapy in such patients.^{1 13}

Severe, occasionally incapacitating bone, joint, and/or muscle pain have been reported infrequently.¹ The time to the onset of symptoms varied from 1 day to several months after treatment initiation.¹ Such pain improves following discontinuance of the drug and may recur upon subsequent rechallenge.¹

Hematologic Effects

Possible anemia; monitor hematocrit and hemoglobin regularly throughout treatment.¹

Respiratory Effects

Possible bronchoconstriction in aspirin-sensitive asthmatic patients.¹ Use with caution in such patients.¹

Specific Populations

Pregnancy

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

Lactation

Not known if zoledronic acid is distributed into milk; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹ Because of long-term retention in bone, use recommended only if the potential benefit from the drug outweighs the possible risk.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

Possible age-related impaired renal function.¹ Careful renal function monitoring recommended.¹

Renal Impairment

Possible renal toxicity.¹

Use in patients with hypercalcemia of malignancy and severe renal impairment only after consideration of other treatment options.^{1 3} Carefully weigh the possible benefits and risks of therapy.^{1 3} Use not recommended in patients with bone metastases and severe renal impairment.^{1 3} (See Renal Effects under Cautions.)

Common Adverse Effects

Patients with hypercalcemia of malignancy: Fever,^{1 2 3 5} nausea,^{1 2 3 5} constipation,^{1 2 3 5} anemia,^{1 2 3 5} dyspnea,^{1 2 3 5} diarrhea,^{1 2 3} progression of cancer,^{1 3} abdominal pain,^{1 2 3} insomnia,^{1 2 3} vomiting,^{1 2 3} urinary tract infection,^{1 3} anxiety,¹ hypophosphatemia,¹ confusion,^{1 2 3 5} agitation,¹ moniliasis,¹ hypokalemia,^{1 2 3 5} skeletal pain,^{1 3} cough,¹ hypotension,¹ hypomagnesemia.¹

Patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma: Nausea,^{1 3 5 7} fatigue,^{1 3 7} anemia,^{1 3 5 7} vomiting,^{1 3 7} fever,^{1 3 5 7} constipation,^{1 3 5 7} dyspnea,^{1 3 5 7} diarrhea,^{1 3 7} myalgia,¹ cough,^{1 7} edema of the lower extremities,^{1 7} arthralgia,^{1 3 7} headache,^{1 3 7} dizziness,^{1 3} weight loss,^{1 3 7} paresthesia,^{1 3} depression,^{1 3} abdominal pain,^{1 3} dehydration,^{1 3} limb pain,¹ decreased appetite,¹ neutropenia,^{1 3} urinary tract infection,^{1 3} hypoesthesia,^{1 3} anxiety,¹ alopecia,^{1 7} dermatitis,^{1 3} rigors,^{1 3} thrombocytopenia,³ dyspepsia,¹ upper respiratory tract infection.¹

Interactions for Zoledronic Acid

Does not inhibit CYP isoenzymes.¹

Nephrotoxic Agents

Potential pharmacologic interaction (increased risk of renal toxicity).¹ Use concomitantly with caution.¹ (See Renal Effects under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Aminoglycosides	Potential for additive effect in lowering serum calcium concentrations1	Such effect not reported1
Loop diuretics	Increased risk of hypocalcemia1	Use caution1
Thalidomide	Potential for increased risk of renal dysfunction in patients with multiple myeloma1

Zoledronic Acid Pharmacokinetics

Absorption

Onset

Hypercalcemia of malignancy: Normocalcemia usually is apparent within 7–10 days.^{1 2 3}

Duration

Hypercalcemia of malignancy: Median time to recurrence (time to last corrected serum calcium concentration of <11.6 mg/dL) was 30 days.¹

Prostate cancer: Bone-related complications not observed within 10.5 months of therapy.¹

Bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Median time to first bone-related complication was 373 days.¹

Bone metastases of solid tumors other than breast or prostate cancer: Median time to the first bone-related complication was 230 days.¹

Special Populations

In adults with mild or moderate renal impairment, the AUC is increased 15 or 43%, respectively, compared with patients with normal renal function.¹

Distribution

Extent

Distributes rapidly to skeletal tissues.¹ Subsequently, the drug is released systemically via bone turnover.¹ Not known whether distributed into breast milk.¹

Plasma Protein Binding

Approximately 22%.¹

Elimination

Metabolism

No evidence of metabolism.¹

Elimination Route

In patients with cancer and bone metastases, excreted in urine (39% within 24 hours) as unchanged drug.¹

Half-life

Terminal half-life is 146 hours.¹

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment and in pediatric patients.¹

Pharmacokinetics not affected by age or race in patients with cancer and bone metastases.¹

Stability

Storage

Parenteral

Solution for Injection

25°C (may be exposed to 15–30°C).¹ Following dilution, 2–8°C; use within 24 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not admix with other agents.¹

Solution Compatibility¹

Compatible
Dextrose 5% in water
Sodium chloride 0.9%
Incompatible
Ringer’s injection, lactated

Actions

• 
  

  Incorporates into bone and selectively inhibits osteoclast-mediated bone resorption.^{1 4 5}

  
  


• 
  

  Inhibits increased osteoclastic activity and skeletal calcium release induced by tumors.¹

  
  


• 
  

  Decreases serum calcium and phosphorus and increases urinary calcium and phosphorus excretion in patients with hypercalcemia of malignancy.¹

  
  

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 3} Advise women of childbearing potential to avoid pregnancy.¹ If 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.

Zoledronic Acid

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, concentrate, for IV infusion	4 mg (of anhydrous zoledronic acid) per 5 mL	Zometa	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Reclast 5MG/100ML Solution (NOVARTIS): 100/$1,137.19 or 300/$3,282.53

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis. Zometa (zoledronic acid) injection prescribing information. East Hanover, NJ; 2005 Apr.

2. Major P, Lortholary A, Han J et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001; 19:558-67. [IDIS 460631] [PubMed 11208851]

3. Novartis Pharmaceuticals, East Hanover, NJ; Personal communication.

4. Brown DL, Robbins R. Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol. 1999; 39:651-60. [IDIS 430233] [PubMed 10392318]

5. Cheer SM, Noble S. Zoledronic acid. Drugs. 2001; 61:799-805. [PubMed 11398911]

6. Anon. Zoledronate (Zometa). Med Lett Drugs Ther. 2001; 43:110-11. [PubMed 11740412]

7. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001; 7:377-87. [PubMed 11693896]

8. Green JR. Chemical and biological prerequisites for novel bisphosphonate molecules: Results of comparative preclinical studies. Semin Oncol. 2001; 28(Suppl. 6):4-10 [PubMed 11346859]

9. Plosker GL, Goa KL. Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs. 1994; 47:945-82. [PubMed 7521833]

10. Coukell AJ, Markham A. Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget’s disease of bone. Drugs Aging. 1998; 12:149-68. [PubMed 9509293]

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

12. Ruggiero SL, Mehrotra B, Rosenberg TJ et al. Osteonecrosis of the jaw associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004; 62:527-34. [IDIS 518769] [PubMed 15122554]

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

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

26. Eidtmann H, Bundred NJ, DeBoer R et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow up of ZO-FAST. Oral presentation at Annual San Antonio Breast Cancer Symposium. San Antonio, TX: 2008 Dec 12. Accessed from website on 12/15/2008.

27. Zoledronic Acid Final Determination. Published May 2008. From AHFS website.

28. Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density study. Lancet Oncol. 2008; 9:840-49. [PubMed 18718815]

10001. Brufsky A, Harker WG, Beck JT et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007; 25: 829-36. [PubMed 17159193]

10002. Brufsky A, Lund K, Cobb P et al. Twenty-four month follow-up of the effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Poster presented at Annual San Antonio Breast Cancer Symposium. San Antonio, TX: 2006 Dec 16. Abstract 5060. Accessed from website on 4/29/2008.

10003. Mincey BA, Dentchev TG, Sloan JA et al. NO3CC- A randomized, controlled, open-label trial of upfront versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with primary breast cancer starting letrozole after tamoxifen. J Clin Oncol. 2008; 26: Abstract No. 564.

10004. Gnant MF, Mlineritsch B, Luschin-Ebengreith G et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2007; 25: 820-8. [PubMed 17159195]

10005. Hillner BE, Ingle JN, Chelebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003; 21:4042-57. [IDIS 513063] [PubMed 12963702]

10006. Eastell R. Breast cancer and the risk of osteoporotic fracture: a paradox. J Clin Endocrinol Metab. 2007; 92: 42-3. [PubMed 17209223]

10007. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA. 2002; 288: 1889-97. [PubMed 12377088]

10008. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab. 2000; 85; 231-6. [PubMed 10634392]

10009. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab. 2002; 87: 1586-92. [PubMed 11932287]

10010. Phase III randomized study of immediate versus delayed zoledronate for prevention of bone loss in postmenopausal women with stage I-IIIA breast cancer initiating letrozole after prior treatment with tamoxifen. Accessed from website on June 4, 2008.

10011. US Food and Drug Administration (FDA). Guidance for preclinical and clinical evaluation of agents used in the prevention of postmenopausal osteoporosis. Rockville, MD: FDA; 1994 Apr.

10012. Gnant MF, Jakesz R, Mlineritsch B et al. Zoledronic acid effectively counteracts cancer treatment induced bone loss in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen—bone density subprotocol results of a randomized multicenter tria

Esclim

Generic Name: estrogen (Oral route, Parenteral route, Topical application route, Transdermal route)

Commonly used brand name(s)

In the U.S.

• Alora


• Cenestin


• Climara


• Divigel


• Elestrin


• Emcyt


• Enjuvia


• Esclim


• Estinyl


• EstroGel


• Evamist


• Femtrace


• Gynodiol


• Menest


• Menostar


• Ogen .625


• Ogen 1.25


• Ogen 2.5


• Premarin


• Vivelle


• Vivelle-Dot

In Canada

• Estraderm


• Estradot Transdermal


• Estradot Transdermal Therapeutic System


• Estradot Transdermal Therapeutic System


• Estrogel


• Oesclim


• Rhoxal-Estradiol Derm 50


• Rhoxal-Estradiol Derm 75


• Roxal-Estradiol Derm 100


• Vivelle 100 Mcg


• Vivelle 25 Mcg

Available Dosage Forms:

• Tablet


• Patch, Extended Release


• Gel/Jelly


• Spray


• Emulsion


• Tablet, Enteric Coated


• Capsule

Uses For Esclim

Estrogens are female hormones. They are produced by the body and are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle during the childbearing years.

The ovaries begin to produce less estrogen after menopause (the change of life). This medicine is prescribed to make up for the lower amount of estrogen. Estrogens help relieve signs of menopause, such as hot flashes and unusual sweating, chills, faintness, or dizziness.

Estrogens are prescribed for several reasons:

• To provide additional hormone when the body does not produce enough of its own, such as during menopause or when female puberty (development of female sexual organs) does not occur on time. Other conditions include a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or ovary problems (female hypogonadism or failure or removal of both ovaries).


• To help prevent weakening of bones (osteoporosis) in women past menopause.


• In the treatment of selected cases of breast cancer in men and women.


• In the treatment of cancer of the prostate in men.

Estrogens may also be used for other conditions as determined by your doctor.

There is no medical evidence to support the belief that the use of estrogens will keep the patient feeling young, keep the skin soft, or delay the appearance of wrinkles. Nor has it been proven that the use of estrogens during menopause will relieve emotional and nervous symptoms, unless these symptoms are caused by other menopausal symptoms, such as hot flashes or hot flushes.

Estrogens are available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, estrogen is used in certain patients with the following medical conditions:

• Gender identity disorder, male-to-female transsexualism (person who is born as a man but adapts to a woman's lifestyle, sees himself as a woman, and feels like a woman instead of a man.


• Osteoporosis caused by lack of estrogen before menopause.


• Turner's syndrome (a genetic disorder).

Before Using Esclim

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of this medicine before puberty is not recommended. Growth of bones can be stopped early. Girls and boys may develop growth of breasts. Girls may have vaginal changes, including vaginal bleeding.

This medicine may be used to start puberty in teenagers with some types of delayed puberty.

Geriatric

Elderly people are especially sensitive to the effects of estrogens. This may increase the chance of side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

Pregnancy

Estrogens are not recommended for use during pregnancy or right after giving birth. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause.

Certain estrogens have been shown to cause serious birth defects in humans and animals. Some daughters of women who took diethylstilbestrol (DES) during pregnancy have developed reproductive (genital) tract problems and, rarely, cancer of the vagina or cervix (opening to the uterus) when they reached childbearing age. Some sons of women who took DES during pregnancy have developed urinary-genital tract problems.

Breast Feeding

Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and their possible effect on the baby is not known.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Rotavirus Vaccine, Live

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine Type 4, Live


• Adenovirus Vaccine Type 7, Live


• Bacillus of Calmette and Guerin Vaccine, Live


• Boceprevir


• Felbamate


• Influenza Virus Vaccine, Live


• Isotretinoin


• Measles Virus Vaccine, Live


• Mumps Virus Vaccine, Live


• Paclitaxel


• Paclitaxel Protein-Bound


• Rotavirus Vaccine, Live


• Rubella Virus Vaccine, Live


• Smallpox Vaccine


• St John's Wort


• Theophylline


• Tizanidine


• Tranexamic Acid


• Typhoid Vaccine


• Varicella Virus Vaccine


• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

For all patients

• Asthma or


• Calcium, too much or too little in blood or


• Diabetes or


• Epilepsy or seizures or


• Heart problems or


• Kidney problems or


• Liver tumors, benign or


• Lupus erythematosus, systemic or


• Migraine headaches—Estrogens may worsen these conditions.

• Blood clotting problems, or history of during previous estrogen therapy—Estrogens usually are not used until blood clotting problems stop; using estrogens is not a problem for most patients without a history of blood clotting problems due to estrogen use.

• Breast cancer or


• Bone cancer or


• Cancer of the uterus or


• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.

• Bulging eyes or


• Double vision or


• Migraine headache or


• Vision changes, sudden onset including or


• Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems, especially while taking estrogen or oral contraceptives (“birth control pills”).

• Changes in genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen condition. The reason for the bleeding should be determined before estrogens are used.

• Endometriosis or


• Gallbladder disease or gallstones, or history of or


• High cholesterol or triglycerides, or history of or


• Liver disease, or history of or


• Pancreatitis (inflammation of pancreas) or


• Porphyria—Estrogens may worsen these conditions. Although estrogens can improve blood cholesterol, they can worsen blood triglycerides for some people.

• Hypothyroid (too little thyroid hormone)—Dose of thyroid medicine may need to be increased.

For males treated for breast or prostate cancer:

• Blood clots or


• Heart or circulation disease or


• Stroke—Males with these medical problems may be more likely to have clotting problems while taking estrogens; the high doses of estrogens used to treat male breast or prostate cancer have been shown to increase the chances of heart attack, phlebitis (inflamed veins) caused by a blood clot, or blood clots in the lungs.

Proper Use of estrogen

This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Esclim. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it and do not take or use it for a longer time than your doctor ordered. For patients taking any of the estrogens by mouth, try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

This medicine usually comes with patient information or directions. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

For patients taking any of the estrogens by mouth or by injection:

• Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

For patients using the transdermal (skin patch):

• Wash and dry your hands thoroughly before and after handling the patch.


• Apply the patch to a clean, dry, non-oily skin area of your lower abdomen, hips below the waist, or buttocks that has little or no hair and is free of cuts or irritation. The manufacturer of the 0.025-mg patch recommends that its patch be applied to the buttocks only. Furthermore, each new patch should be applied to a new site of application. For instance, if the old patch is taken off the left buttock, then apply the new patch to the right buttock.


• Do not apply to the breasts. Also, do not apply to the waistline or anywhere else where tight clothes may rub the patch loose.


• Press the patch firmly in place with the palm of your hand for about 10 seconds. Make sure there is good contact, especially around the edges.


• If a patch becomes loose or falls off, you may reapply it or discard it and apply a new patch.


• Each dose is best applied to a different area of skin on your lower abdomen, hips below the waist, or buttocks so that at least 1 week goes by before the same area is used again. This will help prevent skin irritation.

For patients using the topical emulsion (skin lotion):

• Washing and drying hands thoroughly before each application.


• Apply while you are sitting comfortably. Apply one pouch to each leg every morning.


• Apply the entire contents of one pouch to clean, dry skin on the left thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.


• Apply entire contents of the second pouch to clean, dry skin on the right thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.


• Rub any remaining emulsion on both hands on the buttocks.


• Washing and drying hands thoroughly after application.


• To avoid transfer to other individuals, allow the application areas to dry completely before covering with clothing.

If you are using the Evamist® transdermal spray:

• Spray the medicine on your skin on the inside of your forearm, between the elbow and the wrist.


• Do not allow your child to touch the area of the arm where the medicine was sprayed. If you cannot avoid to come nearer with your child, wear clothes with long sleeves to cover the application site.


• If your child comes in direct contact with the arm where the medicine was sprayed, wash your child's skin right away with soap and water.


• Do not allow your pets to lick or touch the arm where the medicine was sprayed.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For conjugated estrogens


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
    
    
  
  
  • For treating ovary problems (female hypogonadism or for starting puberty):
    
    • Adults and teenagers—0.3 to 0.625 milligram (mg) a day. Your doctor may want you to take the medicine only on certain days of the month.
    
    
  
  
  • For treating ovary problems (failure or removal of both ovaries):
    
    • Adults—1.25 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1.25 to 2.5 milligram (mg) three times a day.
    
    
  
  


• For injection dosage form:
  
  • For controlling abnormal bleeding of the uterus:
    
    • Adults—25 milligrams (mg) injected into a muscle or vein. This may be repeated in six to twelve hours if needed.
    
    
  
  

• For esterified estrogens


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least three months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy) or inflammation of the vagina (atrophic vaginitis), or to prevent loss of bone (osteoporosis):
    
    • Adults—0.3 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (failure or removal of both ovaries):
    
    • Adults—1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism):
    
    • Adults—2.5 to 7.5 mg a day. This dose may be divided up and taken in smaller doses. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—0.625 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1.25 to 2.5 mg three times a day.
    
    
  
  

• For estradiol


• For oral dosage form:
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), ovary problems (female hypogonadism or failure or removal of both ovaries), or symptoms of menopause:
    
    • Adults—At first, 1 to 2 milligrams (mg) one time per day for at least 3 months. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may also need to change the dose based on how your body responds to the medication.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1 to 2 milligrams (mg) three times a day.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.5 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  


• For topical emulsion dosage form (skin lotion):
  
  • For treating symptoms of menopause:
    
    • Adults—1.74 grams (one pouch) applied to the skin of each leg (thigh and calf) once a day in the morning.
    
    
  
  


• For transdermal dosage form (skin patches):
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, ovary problems (female hypogonadism or failure or removal of both ovaries), or to prevent loss of bone (osteoporosis):
    
    • For the Climara patches
    
    
    • Adults—0.025 to 0.1 milligram (mg) (one patch) applied to the skin and worn for one week. Then, remove that patch and apply a new one. A new patch should be applied once a week for three weeks. During the fourth week, you may or may not wear a patch. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    
    
    • For the Alora, Estraderm, Estradot, Vivelle, or Vivelle-Dot patches
    
    
    • Adults—0.025 to 0.1 mg (one patch) applied to the skin and worn for one half of a week. Then, remove that patch and apply and wear a new patch for the rest of the week. A new patch should be applied two times a week for three weeks. During the fourth week, you may or may not apply new patches. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    
    
  
  

• For estradiol cypionate


• For injection dosage form:
  
  • For treating ovary problems (female hypogonadism):
    
    • Adults—1.5 to 2 milligrams (mg) injected into a muscle once a month.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—1 to 5 milligrams (mg) injected into a muscle every 3 to 4 weeks.
    
    
  
  

• For estradiol valerate


• For injection dosage form:
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, or ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—10 to 20 milligrams (mg) injected into a muscle every 4 weeks as needed.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—30 milligrams (mg) injected into a muscle every 1 or 2 weeks.
    
    
  
  

• For estrone


• For injection dosage form:
  
  • For controlling abnormal bleeding of the uterus:
    
    • Adults—2 to 5 milligrams (mg) a day, injected into a muscle for several days.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.1 to 0.5 milligram (mg) injected into a muscle 2 or 3 times a week. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—0.1 to 1 milligram (mg) a week. This is injected into a muscle as a single dose or divided into more than one dose. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—2 to 4 milligrams (mg) injected into a muscle 2 or 3 times a week.
    
    
  
  

• For estropipate


• For oral dosage form (tablets):
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.75 to 6 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—1.5 to 9 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.75 milligram (mg) a day. Your doctor may want you to take the medicine each day for twenty-five days of a thirty-one–day cycle.
    
    
  
  

• For ethinyl estradiol


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—1 milligram (mg) three times a day.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—0.05 milligram (mg) one to three times a day for 3 to 6 months. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—0.15 to 3 milligrams (mg) a day.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—0.02 to 0.05 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  

• For ethinyl estradiol and norethindrone


• For oral dosage form (tablets):
  
  • For treating symptoms of menopause:
    
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Esclim

It is very important that your doctor check your progress at regular visits to make sure this medicine does not cause unwanted effects. These visits will usually be every year, but some doctors require them more often.

In some patients using estrogens, tenderness, swelling, or bleeding of the gums may occur. Brushing and flossing your teeth carefully and regularly and massaging your gums may help prevent this. See your dentist regularly to have your teeth cleaned. Check with your medical doctor or dentist if you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums.

Although the incidence is low, the use of estrogens may increase you chance of getting cancer of the breast, ovaries, or uterus (womb). Therefore, it is very important that you regularly check your breasts for any unusual lumps or discharge. Report any problems to your doctor. You should also have a mammogram (x-ray pictures of the breasts) done if your doctor recommends it. Because breast cancer has occurred in men taking estrogens, regular breast self-exams and exams by your doctor for any unusual lumps or discharge should be done.

If your menstrual periods have stopped, they may start again. This effect will continue for as long as the medicine is taken. However, if taking the continuous treatment (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone once a day), monthly bleeding usually stops within 10 months.

Also, vaginal bleeding between your regular menstrual periods may occur during the first 3 months of use. Do not stop taking your medicine. Check with your doctor if bleeding continues for an unusually long time, if your period has not started within 45 days of your last period, or if you think you are pregnant.

Tell the doctor in charge that you are using this medicine before having any laboratory test because some results may be affected.

Check with your child's doctor right away if your child starts to have the following symptoms: nipple or breast swelling or tenderness in females, or enlargement of the breasts in males. Your child may have been exposed to Evamist® transdermal spray.

Do not allow your pets to lick or touch the arm where Evamist® transdermal spray was applied. Small pets may be sensitive to this medicine. Call your pet's veterinarian if your pet starts to have the following symptoms: nipple or breast enlargement, swelling of the vulva, or any signs of illness.

Esclim Side Effects

Women rarely have severe side effects from taking estrogens to replace estrogen. Discuss these possible effects with your doctor:

The prolonged use of estrogens has been reported to increase the risk of endometrial cancer (cancer of the lining of the uterus) in women after menopause. This risk seems to increase as the dose and the length of use increase. When estrogens are used in low doses for less than 1 year, there is less risk. The risk is also reduced if a progestin (another female hormone) is added to, or replaces part of, your estrogen dose. If the uterus has been removed by surgery (total hysterectomy), there is no risk of endometrial cancer.

Although the incidence is low, the use of estrogens may increase you chance of getting cancer of the breast. Breast cancer has been reported in men taking estrogens.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

The following side effects may be caused by blood clots, which could lead to stroke, heart attack, or death. These side effects occur rarely, and, when they do occur, they occur in men treated for cancer using high doses of estrogens.

Check with your doctor immediately if any of the following side effects occur:

More common

• Breast pain (in females and males)


• fast heartbeat


• fever


• hives


• hoarseness


• increased breast size (in females and males)


• irritation of the skin


• itching of the skin


• joint pain, stiffness, or swelling


• rash


• redness of the skin


• shortness of breath


• swelling of the eyelids, face, lips, hands, or feet


• swelling of the feet and lower legs


• tightness in the chest


• troubled breathing or swallowing


• weight gain (rapid)


• wheezing

Less common or rare

• Changes in vaginal bleeding (spotting, breakthrough bleeding, prolonged or heavier bleeding, or complete stoppage of bleeding)


• chest pain


• chills


• cough


• heavy non-menstrual vaginal bleeding


• lumps in, or discharge from, breast (in females and males)


• pains in the stomach, side, or abdomen


• yellow eyes or skin

Rare - for males being treated for breast or prostate cancer only

• Headache (sudden or severe)


• loss of coordination (sudden)


• loss of vision or change of vision (sudden)


• pains in the chest, groin, or leg, especially in the calf of leg


• shortness of breath (sudden and unexplained)


• slurring of speech (sudden)


• weakness or numbness in the arm or leg

Incidence not known

• Abdominal or stomach bloating


• abdominal or stomach cramps


• acid or sour stomach


• anxiety


• backache


• belching


• blindness


• blistering, peeling, or loosening of the skin


• blue-yellow color blindness


• blurred vision


• change in vaginal discharge


• changes in skin color


• changes in vision


• chest discomfort


• clay-colored stools


• clear or bloody discharge from nipple


• confusion


• constipation


• convulsions


• dark urine


• decrease in the amount of urine


• decreased vision


• depression


• diarrhea


• difficulty with breathing


• difficulty with speaking


• dimpling of the breast skin


• dizziness


• double vision


• dry mouth


• eye pain


• fainting


• fluid-filled skin blisters


• full feeling in upper abdomen or stomach


• full or bloated feeling or pressure in the stomach


• headache


• heartburn


• inability to move the arms, legs, or facial muscles


• inability to speak


• incoherent speech


• increased urination


• indigestion


• inverted nipple


• irregular heartbeats


• light-colored stools


• lightheadedness


• loss of appetite


• loss of bladder control


• lump under the arm


• metallic taste


• migraine headache


• mood or mental changes


• muscle cramps in the hands, arms, feet, legs, or face


• muscle pain


• muscle spasm or jerking of all extremities


• muscle weakness


• nausea


• noisy breathing


• numbness or tingling of the hands, feet, or face


• pain in the ankles or knees


• pain or discomfort in the arms, jaw, back or neck


• pain or feeling of pressure in the pelvis


• pain, tenderness, swelling of the foot or leg


• painful or tender cysts in the breasts


• painful, red lumps under the skin, mostly on the legs


• pains in the chest, groin, or legs, especially calves of the legs


• partial or complete loss of vision in the eye


• pelvic pain


• persistent crusting or scaling of nipple


• pinpoint red or purple spots on the skin


• prominent superficial veins over affected area


• red, irritated eyes


• redness or swelling of the breast


• sensitivity to the sun


• severe headaches of sudden onset


• skin thinness


• skin warmth


• slow speech


• sore on the skin of the breast that does not heal


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• stomach discomfort, upset, or pain


• sudden loss of consciousness


• sudden loss of coordination


• sudden onset of shortness of breath for no apparent reason


• sudden onset of slurred speech


• sudden vision changes


• swelling of the abdominal or stomach area


• swelling of the fingers or hands


• thirst


• tremor


• unpleasant breath odor


• unusual tiredness or weakness


• vomiting


• vomiting of blood


• weight loss

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Abnormal growth filled with fluid or semisolid material


• accidental injury


• bladder pain


• bloated full feeling


• bloody or cloudy urine


• body aches or pain


• coating or white patches on tongue


• congestion


• cough producing mucus


• decrease in amount of urine


• difficult, burning, or painful urination


• discouragement


• dryness of the throat


• ear congestion or pain


• excess air or gas in the stomach or intestines


• fear


• feeling of warmth


• feeling sad or empty


• frequent urge to urinate


• general feeling of discomfort or illness


• headache, severe and throbbing


• increased clear or white vaginal discharge


• irritability


• itching of the vaginal, rectal or genital areas


• lack of appetite


• lack or loss of strength


• loss of interest or pleasure


• mild dizziness


• neck pain


• nervousness


• pain


• pain during sexual intercourse


• painful or difficult urination


• pain or tenderness around the eyes and cheekbones


• passing gas


• redness of the face, neck, arms, and occasionally, upper chest


• runny nose


• skin irritation or redness where skin patch was worn


• shivering


• sleeplessness


• sneezing


• sore mouth or tongue


• stuffy nose


• sudden sweating


• tender, swollen glands in the neck


• thick, white vaginal discharge with no odor or with a mild odor


• tiredness


• trouble concentrating


• trouble sleeping


• unable to sleep


• voice changes

Less common

• Blemishes on the skin


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• burning or stinging of the skin


• diarrhea (mild)


• difficulty with moving


• dizziness (mild)


• increased hair growth, especially on the face


• lower abdominal or stomach pain or pressure


• mood or mental changes


• muscle stiffness


• painful cold sores or blisters on the lips, nose, eyes, or genitals


• pimples


• pounding in the ears


• problems in wearing contact lenses


• slow heartbeat


• tooth or gum pain


• unusual decrease in sexual desire (in males)


• unusual increase in sexual desire (in females)


• white or brownish vaginal discharge

Incidence not known

• Abnormal turning out of cervix


• changes in appetite


• dull ache or feeling of pressure or heaviness in the legs


• flushed, dry skin


• fruit-like breath odor


• increased hunger


• irritability


• large amount of triglyceride in the blood


• leg cramps


• patchy brown or dark brown discoloration of the skin


• poor insight and judgment


• problems with memory or speech


• trouble recognizing objects


• trouble thinking and planning


• trouble walking


• twitching, uncontrolled movements of the tongue, lips, face, arms, or legs


• unexpected or excess milk flow from the breasts

Also, many women who are taking estrogens with a progestin (another female hormone) will start having monthly vaginal bleeding, similar to menstrual periods, again. This effect will continue for as long as the medicine is taken. However, monthly bleeding will not occur in women who have had the uterus removed by surgery (total hysterectomy).

This medicine may cause loss or thinning of the scalp hair in some people.

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

Pramipexole Dihydrochloride

Class: Nonergot-derivative Dopamine Receptor Agonists
VA Class: CN500
Chemical Name: (S)-4,5,6,7-Tetrahydro-N6-propyl,2,6-benzothiazolediamine
Molecular Formula: C₁₀H₁₇N₃S
CAS Number: 104632-26-0
Brands: Mirapex

Introduction

Nonergot-derivative dopamine receptor agonist.^{1 2 3 6 7 8 9 15 16 17 18 19}

Uses for Pramipexole Dihydrochloride

Parkinsonian Syndrome

Symptomatic management of idiopathic parkinsonian syndrome.^{1 2 6 7 8 9 10 13 14 15 16 17 18 19}

Used as an adjunct to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease.^{23 24}

Also used as monotherapy for the initial symptomatic management of parkinsonian syndrome.²³ Most clinicians would use levodopa for initial therapy in individuals >70 years of age (less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease.²³ A dopamine receptor agonist may be preferred for initial therapy in patients ≤70 years of age.²³

Pramipexole Dihydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally, usually in 3 equally divided doses daily.¹

May be administered without regard to meals;²⁰ however, taking the drug with food may reduce the occurrence of nausea.¹

Dosage

Available as pramipexole dihydrochloride; dosage expressed in terms of the monohydrated form of this salt.¹

Adults

Parkinsonian Syndrome

Oral

Initiate at a low dosage and increase slowly (at intervals of ≥5–7 days) until the maximum therapeutic response is achieved.¹

Table 1. Usual Initial Dosage of Pramipexole Dihydrochloride for the Treatment of Parkinsonian Syndrome1

Week of Therapy	Daily Dosage Schedule	Total Daily Dose
1	0.125 mg 3 times daily	0.375 mg daily
2	0.25 mg 3 times daily	0.75 mg daily
3	0.5 mg 3 times daily	1.5 mg daily
4	0.75 mg 3 times daily	2.25 mg daily
5	1 mg 3 times daily	3 mg daily
6	1.25 mg 3 times daily	3.75 mg daily
7	1.5 mg 3 times daily	4.5 mg daily

Continually reevaluate and adjust the dosage according to the needs of the patient in an effort to find a dosage schedule that provides maximum relief of symptoms with minimum adverse effects.^{1 17}

In a fixed-dose study in patients with early parkinsonian syndrome, dosages >1.5 mg daily (i.e., 3, 4.5, or 6 mg daily) were not associated with additional therapeutic benefit.¹ As the dosage increased over the range from 1.5 mg to 6 mg daily, the incidence of postural hypotension, nausea, constipation, somnolence, and amnesia increased.¹

When pramipexole is used as an adjunct to levodopa, consider reducing the levodopa dosage.¹

Discontine pramipexole therapy gradually over a period of 1 week.¹ (See Nervous System and Muscular Effects under Cautions.)

Special Populations

Renal Impairment

Parkinsonian Syndrome

Oral

Modify dosage and/or frequency of administration in response to the degree of renal impairment.^{1 17}

Table 2. Recommended Dosage of Pramipexole Dihydrochloride for Patients with Renal Impairment115

Clcr	Initial Dosage	Maximum Dosage
≥60 mL/minute	0.125 mg 3 times daily	1.5 mg 3 times daily
35–59 mL/minute	0.125 mg twice daily	1.5 mg twice daily
15–34 mL/minute	0.125 mg once daily	1.5 mg once daily
<15 mL/minute	Not adequately studied; no specific recommendation
Hemodialysis	Not adequately studied; no specific recommendation

Geriatric Patients

No dosage adjustments necessary, since therapy is initiated at a low dosage and titrated according to clinical response.¹

Cautions for Pramipexole Dihydrochloride

Contraindications

• 
  

  Known hypersensitivity to pramipexole dihydrochloride or to any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Somnolence

Sudden, irresistible attacks of sleep that resemble narcolepsy have been reported in patients treated with pramipexole.^{1 20 21 22} Episodes of falling asleep while engaged in activities of daily living (e.g., business meetings, telephone calls, driving), which occasionally resulted in accidents, have been reported,^{1 20 21 22 23} in some cases as late as 1 year after initiation of pramipexole therapy.^{1 20 21 22} Some patients perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event;^{1 20 21 22 23} many experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.^{1 20 21 23}

Patients with a history of sleep disorders (e.g., somnolence) or those taking multiple drugs known to cause sedation may be at increased risk of experiencing sudden sleep onset.²⁰ Sleep attacks appear to occur more frequently at higher dosages but may occur at any dosage.²⁰ Somnolence is common at dosages >1.5 mg daily.^{1 20 21}

Patients should not drive or operate other machinery until effects on the individual are known.¹

Continually reassess patients for drowsiness or sleepiness.^{1 20 21 22} Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.^{1 20 21} Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, the presence of sleep disorders, concomitant drugs that increase plasma pramipexole concentrations).^{1 20 21}

Pramipexole generally should be discontinued if a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).^{1 20 21} If the drug is continued, the patient should be advised not to drive and to avoid other potentially dangerous activities.^{1 20 21} Insufficient information to establish that dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.^{1 20 21}

Hallucinations

Potential for hallucinations, particularly in geriatric patients.¹

Symptomatic Hypotension

Dopamine agonists appear to impair systemic regulation of BP in patients with parkinsonian syndrome; patients with parkinsonian syndrome appear to have an impaired capacity to respond to an orthostatic challenge.¹

Use of dopamine agonists in patients with parkinsonian syndrome ordinarily requires careful monitoring for manifestations of orthostatic hypotension, especially during dosage escalation.¹ Unexpectedly, the reported incidence of clinically important orthostatic hypotension with pramipexole did not differ from that with placebo in clinical trials;¹ however, a dose-dependent increase in the incidence of postural hypotension occurs over a pramipexole dihydrochloride dosage range of 1.5–6 mg daily.¹

Caution patients about rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning pramipexole therapy.¹

General Precautions

Rhabdomyolysis

Rhabdomyolysis reported in at least 1 patient with advanced parkinsonian syndrome treated with pramipexole.¹

Nervous System and Muscular Effects

Although not reported in clinical trials with pramipexole, a symptom complex resembling neuroleptic malignant syndrome (e.g., elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with rapid dosage reduction of, withdrawal of, or changes in antiparkinsonian therapy.¹

If pramipexole therapy is discontinued, gradual dosage reduction over a period of 1 week is recommended; in some studies, however, abrupt discontinuance was uneventful.¹

Dyskinesia

May potentiate adverse dopaminergic effects of levodopa and may cause or exacerbate preexisting dyskinesias.^{1 7 8 11 13} Reduction of levodopa dosage may ameliorate dyskinesia.¹

Fibrotic Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of pleura reported in patients receiving ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide);¹ presumably related to the ergoline structure of these agents.¹ Not known whether non-ergot-derived drugs that increase dopaminergic activity (e.g., pramipexole) may induce similar changes.¹

Ocular Effects

Retinal degeneration reported in albino rats receiving pramipexole for 2 years; similar changes not observed in albino mice, monkeys, or minipigs.¹ Clinical importance in humans not established.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Appears to be distributed into milk in rats.¹ Not known whether pramipexole is distributed into human milk.¹ Pramipexole inhibits prolactin secretion.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children.^{1 20}

Geriatric Use

Geriatric patients are at increased risk for hallucinations.¹ No other apparent differences in efficacy or safety between geriatric patients and younger adults.¹

Renal Impairment

Use with caution.¹ Clearance is decreased.¹ Dosage adjustment recommended.^{1 15} (See Renal Impairment under Dosage and Administration.)

Safety and efficacy not evaluated systematically in patients with Cl_cr <15 mL/minute or in those undergoing hemodialysis.¹

Common Adverse Effects

Patients with early parkinsonian syndrome (without levodopa): Nausea, dizziness, somnolence, insomnia, asthenia, constipation, hallucinations, general edema, peripheral edema.¹

Patients with advanced parkinsonian syndrome (with concomitant levodopa): Postural hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, asthenia, constipation, somnolence, dystonia, dry mouth, gait abnormalities, hypertonia, amnesia, urinary frequency.¹

Interactions for Pramipexole Dihydrochloride

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2E1, 3A4, or 2D6 at usual plasma concentrations; is not appreciably metabolized by CYP isoenzymes.¹

Drugs Eliminated via Renal Secretion

Drugs that are secreted by the cationic transport system may decrease the oral clearance of pramipexole by about 20%; those secreted by the anionic transport system are likely to have little effect on the oral clearance of pramipexole.¹

Dopamine Antagonists

Possible pharmacodynamic interaction, resulting in diminished effectiveness of pramipexole.¹

Specific Drugs

Drug	Interaction	Comments
Amantadine	Alteration of oral clearance of pramipexole is unlikely1
Antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes)	Dopamine antagonist activity of the antipsychotic agent may diminish effectiveness of pramipexole1
Cephalosporins	Effect on oral clearance of pramipexole is unlikely1
Chlorpropamide	Effect on oral clearance of pramipexole is unlikely1
Cimetidine	Cimetidine-induced inhibition of renal tubular secretion of organic bases via the cationic transport system increases the AUC and prolongs the half-life of pramipexole1
CNS depressants (e.g., alcohol, antidepressants, antipsychotics, benzodiazepines)	Possible additive sedative effects1 20 21
Diltiazem	Diltiazem is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Hydrochlorothiazide	Effect on oral clearance of pramipexole is unlikely1
Indomethacin	Effect on oral clearance of pramipexole is unlikely1
Levodopa	Additive therapeutic and/or adverse (e.g., dyskinesia) effects; peak plasma levodopa concentration may be higher and occur sooner after administration, but extent of levodopa absorption is not altered1	Consider a reduction in levodopa dosage when pramipexole is added to levodopa therapy1
Metoclopramide	Dopamine antagonist activity of metoclopramide may diminish effectiveness of pramipexole1
Penicillins	Effect on oral clearance of pramipexole is unlikely1
Probenecid	No appreciable alteration of pramipexole pharmacokinetics1
Quinidine and Quinine	Quinidine and quinine are secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Ranitidine	Ranitidine is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Selegiline	Alteration of oral clearance of pramipexole is unlikely1
Triamterene	Triamterene is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Verapamil	Verapamil is secreted by the cationic transport system and may decrease oral clearance of pramipexole1

Pramipexole Dihydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration, with peak plasma concentration attained in approximately 2 hours.¹ Absolute bioavailability is >90%.¹

Food

Food decreases the rate but not the extent of absorption; time to peak concentration is delayed by about 1 hour.^{1 12}

Distribution

Extent

Widely distributed throughout the body.¹

Plasma Protein Binding

15%.¹

Elimination

Metabolism

No metabolites have been identified in plasma or urine.¹

Elimination Route

Eliminated in urine (90%), almost entirely as unchanged drug.¹ Renal clearance of pramipexole is approximately 3 times higher than GFR.¹ Pramipexole is secreted by the renal tubules, probably by the organic cationic transport system.¹

Half-life

Terminal half-life is about 8 hours in young healthy individuals.¹

Special Populations

In individuals >65 years, total oral clearance of pramipexole is reduced by approximately 30% and the terminal half-life is about 12 hours.¹

Pharmacokinetics not evaluated to date in patients with hepatic impairment; however, hepatic impairment would not be expected to have a significant effect on pramipexole elimination, since approximately 90% of a dose is excreted in urine as unchanged drug.¹

In patients with renal impairment, clearance of pramipexole is about 75% lower in patients with Cl_cr of approximately 20 mL/minute and about 60% lower in patients with Cl_cr of approximately 40 mL/minute compared with healthy volunteers.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Protect from light.¹

ActionsActions

• 
  

  Exhibits high binding specificity for and intrinsic activity at dopamine D₂ receptors in vitro compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide);^{3 6 7 8 9 18 19} has a higher affinity for the D₃ subtype¹³ than for the D₂ or D₄ subtypes.^{1 2 9 15 16 19}

  
  


• 
  

  Appears to act by directly stimulating postsynaptic dopamine receptors in the corpus striatum.^{1 6 9 15 16}

  
  

Advice to Patients

• 
  

  Risk of somnolence;¹ possibility of falling asleep while engaged in activities of daily living.^{1 20 21 22 23} Avoid driving or operating machinery until effects on the individual are known.¹

  
  


• 
  

  Potential for orthostatic hypotension (e.g., dizziness, nausea, syncope, sweating), especially during dosage escalation.¹ Patients should avoid rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning pramipexole therapy.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs (especially CNS depressants or alcohol), as well as any concomitant illnesses.¹

  
  


• 
  

  Risk of hallucinations, particularly in geriatric patients.¹

  
  


• 
  

  Pramipexole may be taken with or without food; however, taking the drug with food may reduce the occurrence of nausea.¹

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

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

  
  

Preparations

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

Pramipexole Dihydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	0.125 mg	Mirapex (with povidone)	Pfizer
		0.25 mg	Mirapex (with povidone; scored)	Pfizer
		0.5 mg	Mirapex (with povidone; scored)	Pfizer
		1 mg	Mirapex (with povidone; scored)	Pfizer
		1.5 mg	Mirapex (with povidone; scored)	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mirapex 0.125MG Tablets (BOEHRINGER INGELHEIM): 30/$130.99 or 90/$360.95

Mirapex 0.25MG Tablets (BOEHRINGER INGELHEIM): 90/$349 or 270/$1020.97

Mirapex 0.5MG Tablets (BOEHRINGER INGELHEIM): 90/$336 or 270/$985.96

Mirapex 1MG Tablets (BOEHRINGER INGELHEIM): 90/$336 or 270/$985.96

Mirapex 1.5MG Tablets (BOEHRINGER INGELHEIM): 90/$341 or 270/$974.93

Pramipexole Dihydrochloride 0.125MG Tablets (TEVA PHARMACEUTICALS USA): 30/$85.99 or 90/$239.99

Pramipexole Dihydrochloride 0.25MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 0.5MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 1MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 1.5MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

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 October 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Mirapex (pramipexole dihydrochloride) tablets prescribing information. Kalamazoo, MI; 2003 Jun.

2. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. JAMA. 1997; 278:125-130. [IDIS 388331] [PubMed 9214527]

3. Schilling JC, Adamus WS, Palluk R. Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clin Pharmacol Ther. 1992; 51:541-8. [IDIS 297374] [PubMed 1350237]

4. Eli Lilly and Company. Permax (pergolide mesylate) prescribing information (dated 1995 Feb 15). In: Physicians’ desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:571-3.

5. Sandoz. Parlodel SnapTabs (bromocriptine mesylate) prescribing information (dated 1996 Feb). In: Physicians’ desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:2411-3.

6. Hubble JP, Koller WC, Cutler NR et al. Pramipexole in patients with early Parkinson’s disease. Clin Neuropharmacol. 1995; 18:338-47. [PubMed 8665547]

7. Molho ES, Factor SA, Weiner WJ et al. The use of pramipexole, a novel dopamine (DA) agonist, in advanced Parkinson’s disease. J Neural Transm. 1995; 45(Suppl):225-30.

8. Rabey JM. Second generation of dopamine agonists: pros and cons. J Neural Transm. 1995; 45(Suppl):213-24.

9. Goetz CG. New strategies with dopaminergic drugs: modified formulations of levodopa and novel agonists. Exp Neurol. 1997; 144:17-20. [PubMed 9126145]

10. Shannon KM for the Pramipexole Study Group. Pramipexole monotherapy in early Parkinson’s disease: long-term follow-up and interim analysis. Paper presented at XIIth International Symposium on Parkinson’s Disease. London: World Health Organization; 1997 Mar.

11. Oertel WH, Pogarell O. Long-term follow-up of patients with advanced Parkinson’s disease. Paper presented at XIIth International Symposium on Parkinson’s Disease. London: 1997 Mar.

12. Wright CE, Sisson L, Ichhpurani AK et al. Influence of food on the bioavailability of pramipexole. J Neurol. 1997; 244(Suppl 3):S52.

13. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology. 1997; 49:162-8. [IDIS 388119] [PubMed 9222185]

14. Wright CE, Sisson TL, Ichhpurani AK et al. Pramipexole and levodopa pharmacokinetics following concomitant administration. Neurology. 1997; 48:A185.

15. Wright CE, Sisson L, Ichhpurani AK et al. Influence of renal impairment and hemodialysis on pramipexole pharmacokinetics. Movement Disorders. 1997; 12(Suppl 1):66. [PubMed 8990056]

16. Wright CE, Sisson L, Ichhpurani AK et al. Pramipexole steady-state pharmacokinetics in healthy male and female volunteers. Movement Disorders. 1997; 12(Suppl 1):65.

17. Wright CE, Lasher Sisson T, Ichhpurani AK et al. Influence of age and gender on pramipexole pharmacokinetics. Clin Pharmacol Ther. 1996; 59:184.

18. Albani C, Popescu R, Lacher R et al. Single dose response to pramipexole in patients with Parkinson’s disease. Movement Disorders. 1992; 7(Suppl 1):98.

19. Piercey MF, Hoffmann WE, Smith MW et al. Inhibition of dopamine neuron firing by pramipexole, a dopamine D₃ receptor-preferring agonist: comparison to other dopamine receptor agonists. Eur J Pharmacol. 1996; 312:35-44. [PubMed 8891576]

20. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

21. Gallen CC. Dear healthcare professional letter regarding pramipexole and reports of sudden sleep onset during daily activities. Kalamazoo, MI: Pharmacia & Upjohn; 1999 Aug.

22. Frucht S, Rogers JD, Greene PE et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology. 1999; 52:1908-10. [IDIS 430280] [PubMed 10371546]

23. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology. 2001; 56:S1-S88.

24. Anon. Initial treatment of Parkinson’ disease: wait just a minute. Med Lett Drugs Ther. 2001; 43:59-60. [PubMed 11445778]

More Pramipexole Dihydrochloride resources

• Pramipexole Dihydrochloride Side Effects (in more detail)
• Pramipexole Dihydrochloride Dosage
• Pramipexole Dihydrochloride Use in Pregnancy & Breastfeeding
• Drug Images
• Pramipexole Dihydrochloride Drug Interactions
• Pramipexole Dihydrochloride Support Group
• 46 Reviews for Pramipexole Dihydrochloride - Add your own review/rating

• Pramipexole Prescribing Information (FDA)


• Mirapex Prescribing Information (FDA)


• Mirapex Consumer Overview


• Mirapex Advanced Consumer (Micromedex) - Includes Dosage Information


• Mirapex MedFacts Consumer Leaflet (Wolters Kluwer)


• Mirapex ER Prescribing Information (FDA)


• Mirapex ER Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Pramipexole Dihydrochloride with other medications

• Parkinson's Disease
• Periodic Limb Movement Disorder
• Restless Legs Syndrome
• Tardive Dyskinesia

Liquimat Medium

Generic Name: sulfur topical (SULL fur)

Brand Names: Acnotex, Fostril, Liquimat Light, Liquimat Medium, Rezamid, Sulfo-Lo, Sulfoam, Sulforcin, Sulmasque, Sulpho-Lac, Sulpho-Lac Soap

What is Liquimat Medium (sulfur topical)?

Topical sulfur causes drying and peeling of the skin. This allows excess oil and dirt to be easily washed away.

Sulfur topical is used to treat acne.

Sulfur topical may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Liquimat Medium (sulfur topical)?

Do not use sulfur on sunburned, windburned, dry, chapped, or irritated skin or on open wounds.

Avoid abrasive, harsh, or drying soaps and cleansers while using sulfur topical.

Who should not use Liquimat Medium (sulfur topical)?

Do not use sulfur topical on sunburned, windburned, dry, chapped, or irritated skin. It could make these conditions much worse. Also avoid using sulfur topical on wounds or on areas of eczema. Wait until these conditions have healed before using this medication.

Do not use sulfur topical during treatment with other topical acne products unless otherwise directed with your doctor. The combination could lead to severe skin irritation.

It is not known whether sulfur topical will harm an unborn baby. Do not use sulfur topical without first talking to your doctor if you are pregnant. It is also not known whether sulfur passes into breast milk. Do not use sulfur topical without first talking to your doctor if you are breast-feeding a baby.

How should I use Liquimat Medium (sulfur topical)?

Use sulfur topical exactly as directed by your doctor, or follow the instructions that accompany the package. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Wash your hands before and after applying this medication.

Shake lotions well before using them. Clean and dry the area to which you will apply sulfur topical. Apply the medication to the affected area. When applying sulfur topical, avoid your eyes, the inside of your nose and mouth, your lips, and areas where the skin is broken to prevent excessive irritation. If you get medication in any of these areas, rinse it off with water.

Do not cover the affected area after applying sulfur topical, unless otherwise directed by your doctor. Doing so could cause too much medicine to be absorbed by your body and could be harmful.

Sulfur topical is usually applied one to three times daily.

It may take several weeks or more to see the effects of this drug. Do not stop using sulfur topical if you do not see results immediately.

Apply sulfur topical less often if you experience excessive burning, dryness, or irritation.

Store sulfur topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the dose you missed and apply only your next regularly scheduled dose.

What happens if I overdose?

An overdose of sulfur topical is unlikely to occur. If you do suspect an overdose, or if sulfur topical has been ingested, call a poison control center or emergency room for advice.

What should I avoid while using Liquimat Medium (sulfur topical)?

Do not use sulfur topical on sunburned, windburned, dry, chapped, or irritated skin or on open wounds.

Avoid using other topical products on the same area unless otherwise directed to do so by your doctor. They may interfere with the effects or absorption of sulfur topical.

Do not cover the area after applying sulfur topical, unless otherwise directed by your doctor. Doing so could cause too much medicine to be absorbed by your body and could be harmful.

Avoid using harsh, abrasive or irritating cleansers, perfumes or cosmetics on the area you are treating.

Liquimat Medium (sulfur topical) side effects

Serious side effects are not likely to occur. Stop using sulfur topical and seek emergency medical attention if you experience an allergic reaction (shortness of breath; closing of your throat; swelling of your lips, face, or tongue; or hives).

You may experience some burning, stinging, tingling, itching, redness, dryness, peeling, or irritation while you are using sulfur topical. If these side effects are excessive, apply sulfur topical less often.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Liquimat Medium (sulfur topical)?

Do not use other topical preparations unless directed to do so by your doctor. They may interfere with your treatment or increase irritation to your skin.

Avoid using harsh, abrasive or irritating cleansers, perfumes, or cosmetics on the area you are treating.

Drugs other than those listed here may also interact with sulfur topical. Talk to your doctor and pharmacist before taking any prescription or over the counter medicines.

More Liquimat Medium resources

• Liquimat Medium Side Effects (in more detail)
• Liquimat Medium Use in Pregnancy & Breastfeeding
• Liquimat Medium Drug Interactions
• Liquimat Medium Support Group
• 0 Reviews for Liquimat Medium - Add your own review/rating

• Sulfo-Lo Topical Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Liquimat Medium with other medications

• Acne

Where can I get more information?

• Your pharmacist has additional information about sulfur topical written for health professionals that you may read.

See also: Liquimat Medium side effects (in more detail)