Ixabepilone

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (1S,3S,7S,10R,11S,12S,16R) - 7,11 - dihydroxy - 8,8,10,12,16 - pentamethyl - 3 - [(1E) - 1 - methyl - 2 - (2 - methyl - 4 - thiazolyl)ethenyl] - 17 - oxa - 4 - azabicyclo[14.1.0] heptadecane-5,9-dione
Molecular Formula: C₂₇H₄₂N₂O₅S
CAS Number: 219989-84-1
Brands: Ixempra

• Toxicity in Hepatic Impairment


• 
  

  Increased risk of toxicity and neutropenia-related death in patients with AST or ALT >2.5 times upper limit of normal (ULN) or bilirubin >1 times ULN in combination with oral capecitabine;¹ concomitant use of ixabepilone and capecitabine not recommended in these patients.¹ (See Hepatic Impairment and also see Contraindications under Cautions.)

  
  

Introduction

Antineoplastic agent; semisynthetic derivative of epothilone B; a microtubule inhibitor.^{1 2 3 5 6 7 9 10 11 13 15 17 18 19}

Uses for Ixabepilone

Breast Cancer

Treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.^{1 2 5 7 11 13 17}

Used in combination with oral capecitabine for treatment of metastatic or locally advanced breast cancer in patients whose disease is resistant to treatment with an anthracycline and a taxane or in patients whose cancer is taxane-resistant and for whom further anthracycline therapy is contraindicated.^{1 2 8 11 13 17}

Under investigation for initial therapy of advanced breast cancer†.^{11 13}

Ixabepilone Dosage and Administration

General

• 
  

  To minimize risk of hypersensitivity reactions, premedicate with diphenhydramine 50 mg orally (or a similar antihistamine) and an H₂-receptor antagonist (e.g., ranitidine 150–300 mg orally) 1 hour before the infusion.^{1 2} (See Hypersensitivity Reactions under Cautions.)

  
  


• 
  

  In patients who experienced a prior hypersensitivity reaction to the drug, premedicate with corticosteroids (e.g., dexamethasone 20 mg either IV 30 minutes prior to infusion or orally 60 minutes prior to infusion) in addition to pretreatment with an antihistamine and an H₂-receptor antagonist.^{1 2}

  
  


• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{1 14}

  
  

Administration

IV Administration

Administer by IV infusion.^{1 2}

Administer through an appropriate 0.2- to 1.2-mcm inline filter.^{1 2} Use only diethylhexylphthalate (DEHP)-free infusion containers and administration sets.^{1 2}

Handle cautiously; use protective equipment (e.g., latex gloves) to minimize risk of dermal exposure.¹

Prior to administration, reconstitute powder for injection and dilute.¹

Reconstitution

Prior to reconstitution, remove kit from the refrigerator and allow to stand at room temperature for approximately 30 minutes.¹ When first removed from the refrigerator, a white precipitate may be visible in diluent vial, but precipitate will dissolve to form a clear solution once the diluent warms to room temperature.^{1 2}

Reconstitute powder for injection by slowly adding 8 or 23.5 mL of the supplied diluent to the vial labeled as containing 15 or 45 mg, respectively, to provide a solution containing 2 mg/mL.^{1 2} Gently swirl the vial and invert until the powder completely dissolves.¹ Use only the diluent provided by the manufacturer for reconstitution.¹

Following reconstitution, must be diluted further with an appropriate infusion solution as soon as possible; reconstituted solution may be stored in vial for ≤1 hour at room temperature and room light.^{1 2 c}

Dilution

Withdraw the appropriate dose and dilute in appropriate volume of lactated Ringer’s injection, 0.9% sodium chloride injection (pH adjusted), or Plasma-Lyte A injection supplied in diethylhexylphthalate (DEHP)-free bags.^c Usually, a 250-mL bag of infusion solution is sufficient; however, verify the final infusion concentration of each dose based on the volume of infusion solution used; final infusion concentration must be between 0.2–0.6 mg/mL.^{2 c} Mix the infusion bag thoroughly by manual rotation.¹

If 0.9% sodium chloride injection is used as infusion solution, must adjust pH to 6–9 by adding 2 mEq sodium bicarbonate injection (i.e., 2 mL of 8.4% w/v or 4 mL of 4.2% w/v solution) prior to adding reconstituted dose.^c

Following dilution, solution is stable at room temperature and room light for ≤6 hours; complete administration of diluted ixabepilone must occur within this 6-hour period.^{1 2}

Rate of Administration

Administer over 3 hours.¹

Dosage

Adults

Breast Cancer

IV

40 mg/m² every 3 weeks.^{1 2 7 17 18}

Body surface area >2.2 m²: Calculate dosage based on 2.2 m².¹

Adjustments necessary when used in conjunction with potent inhibitors of CYP3A4.¹ (See Interactions.)

Dosage Modification for Toxicity

Nonhematologic Adverse Effects

If moderate to severe neuropathy or any other severe nonhematologic toxicity occurs, withhold ixabepilone until the event improves to grade 1 or resolves.^c Thereafter, resume therapy, as appropriate, at a reduced dosage depending on the severity of the event in the previous cycle.^c (See Table 1.)

Dosage adjustments at the start of a course of therapy should be based on nonhematologic toxicity from previous cycle.¹

NCIC Common Toxicity Criteria.¹

Table 1. Recommended Dosage Modifications for Nonhematologic Toxicity with Ixabepilone Monotherapy or Combination Therapy

Nonhematologic Toxicity	Dosage Adjustment
Grade 2 neuropathy (moderate) lasting ≥7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Grade 3 neuropathy (severe) lasting <7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy	Discontinue therapy
Any grade 3 toxicity (severe) other than neuropathy	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Transient grade 3 arthralgia/myalgia or fatigue	No change in ixabepilone dosage
Any grade 4 toxicity (disabling)	Discontinue therapy

Adverse Hematologic Effects

If severe neutropenia and/or thrombocytopenia occurs, withhold ixabepilone until ANC ≥1500/mm³ and platelets ≥100,000/mm³.^c Thereafter, resume therapy, as appropriate, at a reduced dosage.^c (See Table 2.)

Dosage adjustments at the start of a course of therapy should be based on blood cell counts from previous cycle.¹

Table 2. Recommended Dosage Modifications for Hematologic Toxicity with Ixabepilone Monotherapy or Combination Therapy

Hematologic Measurements	Dosage Adjustment	Comments
ANC <500/mm3 for ≥7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%c	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until ANC >1000/mm3c
Febrile neutropenia	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%c	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until ANC >1000/mm3c
Platelets <25,000/mm3	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%c	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until platelet count >50,000/mm3c
Platelets <50,000/mm3 with bleeding	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%c	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until platelet count >50,000/mm3c

Special Populations

Hepatic Impairment

Prior to initiation and periodically thereafter assess hepatic function; dosage adjustment recommended based on hepatic function.¹ (See Table 3.)

Breast Cancer

Monotherapy

Use not recommended in patients with AST and ALT >10 times ULN and bilirubin >3 times ULN.^c Use with caution in patients with AST and ALT >5 times ULN.^c

Adjust dosage based on degree of hepatic impairment (i.e., transaminase and bilirubin concentrations).^c (See Table 3.)

Excludes patients whose total bilirubin is elevated due to Gilbert’s disease.¹

Dosage recommendations are for first course of therapy; further dosage decreases in subsequent courses should be made based on individual tolerance.¹

Table 3. Dosage Adjustments for Ixabepilone Monotherapy in Patients with Hepatic Impairment120

Severity	Transaminase Concentrations	Bilirubin Concentrations	Dosage
Mild	AST and ALT ≤2.5 times ULN	≤1 times ULN	40 mg/m2 every 3 weeks
	AST and ALT ≤10 times ULN	≤1.5 times ULN	32 mg/m2 every 3 weeks
Moderate	AST and ALT ≤10 times ULN	>1.5 times ULN to ≤3 times ULN	Initially, 20 mg/m2 every 3 weeks; subsequently, dosage may be increased to a maximum 30 mg/m2, if toleratedc

Combination Therapy with Capecitabine

Contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin >1 times ULN.^c

Patients with AST and ALT ≤2.5 times ULN and bilirubin ≤1 times ULN: 40 mg/m².¹

Renal Impairment

No specific dosage recommendations for patients with renal impairment.^{1 2}

Cautions for Ixabepilone

Contraindications

• 
  

  History of severe (grade 3 or 4) hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil).^{1 2}

  
  


• 
  

  Neutrophil count <1500/mm³ or platelet count <100,000/mm³.¹

  
  


• 
  

  Use in combination with capecitabine contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin elevated above ULN (i.e., >1 times ULN).^{1 7}

  
  

Warnings/Precautions

Warnings

Peripheral Neuropathy

Peripheral neuropathy occurs commonly; usually develops early during treatment (e.g., during the first 3 cycles).^{1 3 16 17}

Monitor patients for symptoms of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain).¹ Dosage reduction or delay in therapy may be required in patients experiencing new or worsening symptoms.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Increased risk of severe neuropathy in patients with diabetes mellitus or preexisting peripheral neuropathy; use with caution.^{1 c}

Hematologic Effects

Risk of dose-limiting, potentially fatal myelosuppression, manifested primarily as neutropenia.¹ Leukopenia, anemia, and thrombocytopenia also reported.^{1 2 3 13 17}

Monitor peripheral blood cell counts frequently during therapy.¹

Dosage reduction recommended in patients experiencing severe neutropenia or thrombocytopenia.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Contraindicated in patients with a neutrophil count <1500/mm³ or platelet count <100,000/mm³.¹ (See Contraindications.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Cardiovascular Effects

Increased risk of adverse cardiac reactions (myocardial ischemia, ventricular dysfunction, supraventricular arrhythmias) in combination with capecitabine.^{1 c}

Use with caution in patients with a history of cardiac disease.¹ Consider discontinuance of therapy in patients who develop cardiac ischemia or impaired cardiac function.¹

CNS Effects

Diluent in the commercially available Ixempra kit contains dehydrated alcohol; consider possibility of adverse CNS effects (e.g., cognitive impairment and other effects of alcohol).¹ (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions, including anaphylaxis, reported. ^c

Premedicate patients with an antihistamine and an H₂-receptor antagonist approximately 1 hour before beginning the infusion; observe for hypersensitivity reactions (e.g., flushing, rash, dyspnea, bronchospasm).^{1 2 17}

If severe hypersensitivity reaction occurs, discontinue immediately and institute aggressive supportive treatment (e.g., epinephrine, corticosteroids).¹ Premedicate patients who experienced a hypersensitivity reaction during a previous cycle with a corticosteroid (in addition to an antihistamine and an H₂-receptor antagonist) and consider increasing infusion time.¹

Contraindicated in patients with a history of severe hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil), such as paclitaxel.^{1 2} (See Contraindications.)

Other Warnings/Precautions

Adequate Patient Evaluation and Monitoring

Evaluate patients during therapy by periodic clinical observation and laboratory tests, including CBCs and hepatic function.¹ Patients must have recovered from acute toxicities (e.g., neutrophils >1500/mm³, platelets >100,000/mm³, nonhematologic toxicities improved to grade 1) before each cycle.^c (See Dosage Modification for Toxicity under Dosage and Administration.)

Specific Populations

Pregnancy

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

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^c Discontinue nursing or the drug.^{1 b}

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.^{1 20}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹

In combination with capecitabine, increased incidence of grade 3 or 4 adverse reactions in patients ≥65 years of age compared with younger adults.^c When used as monotherapy, no overall differences in safety observed in patients ≥65 years of age compared with younger adults.¹

Hepatic Impairment

Increased risk of serious toxicity in patients with baseline AST or ALT >2.5 times ULN or bilirubin >1.5 times ULN.^{1 9} Monitor hepatic function prior to initiation of therapy and periodically thereafter.^c

Use in combination with capecitabine contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin >1 times ULN.^{1 7}

Use as monotherapy in patients with AST or ALT >10 times ULN or bilirubin >3 times ULN not recommended.¹ Limited data available for patients with AST or ALT >5 times ULN; use with caution in these patients.¹

Dosage reduction recommended if used as monotherapy in patients with hepatic impairment.¹ (See Special Populations under Dosage and Administration.)

Renal Impairment

Pharmacokinetics not evaluated; however, when used as monotherapy, impact of mild to moderate renal impairment (Cl_cr >30 mL/min) should be minimal.^c

Common Adverse Effects

Ixabepilone monotherapy: Peripheral sensory neuropathy, myelosuppression, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, musculoskeletal pain.^{1 2 5 13 15 17}

Ixabepilone in combination with capecitabine: Peripheral sensory neuropathy, myelosuppression, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, musculoskeletal pain, palmar-plantar erythrodysesthesia (hand-foot syndrome), anorexia, abdominal pain, nail disorder, constipation.^{1 3 13}

Interactions for Ixabepilone

Metabolized principally by CYP3A4.¹ Pharmacokinetic interactions with inhibitors or inducers of CYP3A4 are likely.^{1 c}

Does not inhibit CYP isoenzymes 3A4, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2D6; does not induce CYP isoenzymes 3A4, 1A2, 2B6, or 2C9.^{1 c} Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.^{9 17 c}

Substrates of CYP isoenzymes: Pharmacokinetic interaction unlikely when used in combination with substrates of these isoenzymes.^{1 9 17}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma ixabepilone concentrations).¹ Avoid concomitant use with potent CYP3A4 inhibitors;¹ if concomitant therapy is necessary, monitor closely for toxicity and reduce ixabepilone dosage.^{1 2} (See Specific Drugs and Foods under Interactions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma ixabepilone concentrations);^{1 17} if concomitant therapy necessary, consider alternative drugs with less enzyme induction potential.¹ (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Decreased plasma ixabepilone concentrations1	Potential for subtherapeutic ixabepilone concentrations; consider alternative drugs with low enzyme induction potential1
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Increased plasma ixabepilone concentrations1 7 12 13	Avoid concomitant use with itraconazole, ketoconazole, and voriconazole; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m2;1 2 if azole antifungal is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m21 2 Fluconazole: Effects from concomitant use not studied; 1 use concomitantly with caution; consider alternative agents and monitor closely for toxicity (e.g., peripheral blood counts between cycles)1
Antimycobacterials (rifampin, rifabutin)	Decreased plasma ixabepilone concentrations1	Potential subtherapeutic ixabepilone concentrations; consider alternative drugs with low enzyme induction potential1
Capecitabine	Decreased plasma ixabepilone and capecitabine concentrations1	Interaction unlikely to be clinically important; effectiveness of combination therapy demonstrated in clinical trials1 3 7 11
Delavirdine	Increased plasma ixabepilone concentrations1 7 12 13	Avoid concomitant use; 1 7 12 13 if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m2;1 2 if delavirdine is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m21 2
Dexamethasone	Decreased plasma ixabepilone concentrations1	Potential subtherapeutic ixabepilone concentrations; consider alternative drugs with low enzyme induction potential1
Grapefruit	Increased plasma ixabepilone concentrations1 2	Avoid concomitant use of grapefruit juice1
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Increased plasma ixabepilone concentrations1 7 12 13	Avoid concomitant use;1 7 12 13 if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m2;1 2 if HIV protease inhibitor is discontinued, allow 1 week to elaspe before increasing ixabepilone dosage to 40 mg/m21 2
Macrolides (e.g., clarithromycin, erythromycin, telithromycin)	Increased plasma ixabepilone concentrations1 7 12 13	Avoid concomitant use with clarithromycin and telithromycin; 1 7 12 13 if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m2;1 2 if macrolide is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m21 2 Erythromycin: Effects from concomitant use not studied; 1 use concomitantly with caution; consider alternative agents and monitor closely for acute toxicity (e.g., peripheral blood counts between cycles)1
Nefazodone	Increased plasma ixabepilone concentrations1 7 12 13	Avoid concomitant use; 1 7 12 13 if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m2;1 2 if nefazodone is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m21 2
St. John’s wort (Hypericum perforatum)	Possible unpredictable decreased plasma ixabepilone concentrations1	Avoid concomitant use1
Verapamil	Possible increased plasma ixabepilone concentrations1	Effects from concomitant use not studied; use concomitantly with caution; consider alternative agents and monitor closely for acute toxicity (e.g., peripheral blood counts between cycles)1

Ixabepilone Pharmacokinetics

Absorption

Bioavailability

Peak concentrations usually attained at end of 3-hour infusion.¹

Distribution

Extent

Not known if ixabepilone is distributed into human milk.¹

Plasma Protein Binding

67–77%.^c

Elimination

Metabolism

Extensively metabolized in the liver, principally by oxidative metabolism via CYP3A4.^{1 2 13 17}

Elimination Route

86% of an IV dose is excreted in feces (65%) and urine (21%) primarily as metabolites;^{1 9 17} unchanged drug accounted for <2 and 6% of the dose in feces and urine, respectively.^{1 2 9}

Half-life

Approximately 52 hours (range: 20–72 hours).^{1 2 11 13 17}

No accumulation in plasma expected when administered once every 3 weeks.^{1 2}

Special Populations

Gender, race, and age do not have meaningful effects on pharmacokinetics of ixabepilone.¹

Stability

Storage

Parenteral

Powder for Injection

2–8° C in original package; protect from light.¹

ActionsActions

• 
  

  A microtubule inhibitor; binds to β-tubulin subunits on microtubules; stabilizes and suppresses microtubule activity resulting in mitotic arrest and apoptosis.^{1 13 15 17 18 19}

  
  


• 
  

  Active in xenografts resistant to multiple antineoplastic agents, including taxanes, anthracyclines, and vinca alkaloids.^{1 13 19}

  
  


• 
  

  Synergistic antitumor activity demonstrated in combination with capecitabine in vivo.¹

  
  


• 
  

  Has antiangiogenic activity.¹

  
  

Advice to Patients

• 
  

  Importance of reading patient information provided by the manufacturer.^{1 b}

  
  


• 
  

  Importance of patients notifying clinicians if they develop any numbness, tingling, or burning of the hands or feet.^{1 2 b}

  
  


• 
  

  Importance of patients notifying clinicians if they develop a fever of ≥38°C or other signs and symptoms of potential infection (e.g., chills, cough, burning or pain upon urination).^{1 2 b}

  
  


• 
  

  Importance of patients notifying clinicians if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness, and/or other hypersensitivity-related symptoms following IV infusion of ixabepilone.^{1 b}

  
  


• 
  

  Importance of patients notifying clinicians if they notice chest pain, difficulty breathing, palpitations, or unusual weight gain.^{1 b}

  
  


• 
  

  Importance of patients informing clinicians if they are allergic to a drug such as paclitaxel that contains polyoxyl 35 castor oil (Cremophor EL, polyethoxylated castor oil).^{1 2 b}

  
  


• 
  

  Importance of not drinking grapefruit juice while receiving ixabepilone therapy.^{1 2 b}

  
  


• 
  

  Importance of informing patients that Ixempra contains alcohol and may cause drowsiness or dizziness.^{1 b} Importance of avoiding certain activities (e.g., operating machinery, driving a motor vehicle) if patient feels drowsy or dizzy.^b

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary (e.g., grapefruit) or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., diabetes mellitus, liver disease).^{1 2 b}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.^{1 b}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 b} (See Cautions.)

  
  

Preparations

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

Ixabepilone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion only	15 mg	Ixempra	Bristol-Myers Squibb
		45 mg	Ixempra	Bristol-Myers Squibb

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 May 2010. 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. Bristol-Myers Squibb Company. Ixempra (ixabepilone) Kit for injection prescribing information. Princeton, NJ; 2007 Oct.

2. Bhushan S, Walko CM. Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer. Ann Pharmacother. 2008; 42:1252-61. [PubMed 18648018]

3. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007; 25:5210-7. [PubMed 17968020]

4. Thomas ES. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2008; 26:2223. [PubMed 18445853]

5. Perez EA, Lerzo G, Pivot X et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007; 25:3407-14. [PubMed 17606974]

6. Thomas E, Tabernero J, Fornier M et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007; 25:3399-406. [PubMed 17606975]

7. Moulder SL. Ixabepilone for the treatment of taxane-refractory breast cancer. Future Oncol. 2008; 4:333-40. [PubMed 18518758]

8. Lechleider RJ, Kaminskas E, Jiang X et al. Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clin Cancer Res. 2008; 14:4378-84. [PubMed 18628451]

9. Higa GM, Abraham J. Ixabepilone: a new microtubule-targeting agent for breast cancer. Expert Rev Anticancer Ther. 2008; 8:671-81. [PubMed 18471040]

10. Pivot X, Villanueva C, Chaigneau L et al. Ixabepilone, a novel epothilone analog in the treatment of breast cancer. Expert Opin Investig Drugs. 2008; 17:593-9. [PubMed 18363523]

11. Denduluri N, Swain SM. Ixabepilone for the treatment of solid tumors: a review of clinical data. Expert Opin Investig Drugs. 2008; 17:423-35. [PubMed 18321240]

12. Goel S, Cohen M, Cömezoglu SN et al. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res. 2008; 25:2701-9.

13. Trivedi M, Budihardjo I, Loureiro K et al. Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer. Future Oncol. 2008; 4:483-500. [PubMed 18684060]

14. Institute for Safe Medication Practices. ISMP’s list of high-alert medications. Horsham, PA; 2008. From ISMP website (). Accessed 2008 Sep 23.

15. Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol. 2008; 6:455-67. [PubMed 18567992]

16. Lee JJ, Low JA, Croarkin E et al. Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone. Expert Opin Investig Drugs. 2006; 24:2084-91.

17. Anon. Ixabepilone (Ixempra) for breast cancer. Med Lett Drugs Ther. 2008; 50:7-8. [PubMed 18219261]

18. Goodin S. Novel cytotoxic agents: epothilones. Am J Health-Syst Pharm. 2008; 65 (Suppl 3):S10-5.

19. Pronzato P. New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones. Drugs. 2008; 68:139-46. [PubMed 18197722]

20. Bristol-Myers Squibb Company. Princeton, NJ: Personal communication.

a. AHFS drug information 2009. McEvoy GK, ed. Ixabepilone. Bethesda, MD: American Society of Health-System Pharmacists; 2009: 1136–9.

b. Bristol-Myers Squibb Company. Ixempra (ixabepilone) Kit for injection patient information. Princeton, NJ; 2007 Oct.

c. Bristol-Myers Squibb Company. Ixempra (ixabepilone) Kit for injection prescribing information. Princeton, NJ; 2009 Mayt.

More Ixabepilone resources

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

• Ixabepilone MedFacts Consumer Leaflet (Wolters Kluwer)


• Ixabepilone Professional Patient Advice (Wolters Kluwer)


• ixabepilone Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Ixempra Prescribing Information (FDA)


• Ixempra Consumer Overview

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Mirena Dosage and Administration

Mirena contains 52 mg of levonorgestrel. Initially, levonorgestrel is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years.

Mirena is packaged sterile within an inserter. Information regarding insertion instructions, patient counseling and record keeping, patient follow-up, removal of Mirena and continuation of contraception after removal is provided below.

. Insertion Instructions

• NOTE: Mirena should be inserted by a trained healthcare provider. Healthcare providers are advised to become thoroughly familiar with the insertion instructions before attempting insertion of Mirena.


• Mirena is inserted with the provided inserter (Figure 1a)  into the uterine cavity within seven days of the onset of menstruation or immediately after a first trimester abortion by carefully following the insertion instructions. It can be replaced by a new Mirena at any time during the menstrual cycle.


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  Figure 1a. Mirena and inserter

  
  
  
  

Preparation for insertion

• Ensure that the patient understands the contents of the Patient Information Booklet and obtain consent. A consent form that includes the lot number is on the last page of the Patient Information Booklet.


• Confirm that there are no contraindications to the use of Mirena.


• Perform a urine pregnancy test, if indicated.


• With the patient comfortably in lithotomy position, gently insert a speculum to visualize the cervix and rule out genital contraindications to the use of Mirena.


• Do a bimanual exam to establish the size and position of the uterus, to detect other genital contraindications, and to exclude pregnancy.


• Thoroughly cleanse the cervix and vagina with a suitable antiseptic solution. Perform a paracervical block, if needed.


• Prepare to sound the uterine cavity. Grasp the upper lip of the cervix with a tenaculum forceps and apply gentle traction to align the cervical canal with the uterine cavity. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. Note that the tenaculum forceps should remain in position throughout the insertion procedure to maintain gentle traction on the cervix.


• Gently insert a uterine sound to check the patency of the cervix, measure the depth of the uterine cavity, confirm its direction and exclude the presence of any uterine anomaly. If you encounter cervical stenosis, use dilatation, not force, to overcome resistance.


• The uterus should sound to a depth of 6 to 10 cm. Insertion of Mirena into a uterine cavity less than 6 cm by sounding may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy.


• After ascertaining that the patient is appropriate for Mirena, open the carton containing Mirena.

Insertion Procedure

Ensure use of sterile technique throughout the entire procedure.

Step 1–Opening of the sterile package

• Open the sterile package completely (Figure 1b).


• Place sterile gloves on your hands.


• Pick up the handle of the inserter containing Mirena and carefully release the threads so that they hang freely.

Place your thumb or forefinger on the slider. Make sure that the slider is in the furthest position away from you, for example, at the top of the handle towards the insertion tube (Figure 1b).

NOTE: Keep your thumb or forefinger on the slider until insertion is complete.

• With the centimeter scale of the insertion tube facing up, check that the arms of Mirena are in a horizontal position. If they are not, align them on a flat, sterile surface, for example, the sterile package (Figures 1b and 1c).


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  Figure 1b. Aligning the arms with the slider in the furthest position

  
  
  
  


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  Figure 1c. Checking that the arms are horizontal and aligned with respect to the scale

  
  
  
  

Step 2–Load Mirena into the insertion tube

• Holding the slider in the furthest position, pull on both threads to load Mirena into the insertion tube (Figure 2a).


• Note that the knobs at the ends of the arms now meet to close the open end of the insertion tube (Figure 2b).
  

  If the knobs do not meet properly

  
  

If the knobs do not meet properly, release the arms by pulling the slider back to the mark (raised horizontal line on the handle) (Figure 6a) . Re-load Mirena by aligning the open arms on a sterile surface (Figure 1b). Return the slider to its furthermost position and pull on both threads. Check for proper loading (Figure 2b).

Figure 2a. Loading Mirena into the insertion tube

Figure 2b. Properly loaded Mirena with knobs closing the end of the insertion tube

Step 3–Secure the threads

Secure the threads in the cleft at the bottom end of the handle to keep Mirena in the loaded position (Figure 3).

Figure 3. Threads are secured in the cleft

Step 4–Setting the flange

Set the upper edge of the flange to the depth measured during the uterine sounding (Figure 4). 

 

Figure 4. Setting the flange to the uterine depth

 Step 5–Mirena is now ready to be inserted

• Continue to hold the slider with the thumb or forefinger firmly in the furthermost position. Grasp the tenaculum forceps with your other hand and apply gentle traction to align the cervical canal with the uterine cavity.


• While maintaining traction on the cervix, gently advance the insertion tube through the cervical canal and into the uterine cavity until the flange is 1.5 to 2 cm from the external cervical os.


• CAUTION: do not advance flange to the cervix at this step. Maintaining the flange 1.5 to 2 cm from the cervical os allows sufficient space for the arms to open (when released) within the uterine cavity (Figures 5 and 6b).
  

  NOTE! Do not force the inserter. If necessary, dilate the cervical canal.

  
  

Figure 5. Advancing insertion tube until flange is 1.5 to 2 cm from cervical os

Step 6–Release the arms

• While holding the inserter steady, release the arms of Mirena by pulling the slider back until the top of the slider reaches the mark (raised horizontal line on the handle) (Figure 6a).


• Wait approximately 10 seconds to allow the horizontal arms of Mirena to open and regain its T-shape (Figure 6b).

Figure 6a. Pulling the slider back to reach the mark

Figure 6b. Releasing the arms of Mirena

Step 7–Advance to fundal position

Gently advance the inserter into the uterine cavity until the flange meets the cervix and you feel fundal resistance. Mirena should now be in the desired fundal position (Figure 7).

Figure 7. Mirena in the fundal position

Step 8–Release Mirena and withdraw the inserter

• While holding the inserter steady, pull the slider all the way down to release Mirena from the insertion tube (Figure 8). The threads will release automatically from the cleft.


• Check that the threads are hanging freely and gently withdraw the inserter from the uterus. Be careful not to pull on the threads as this will displace Mirena.

Figure 8. Releasing Mirena from the insertion tube

Step 9–Cut the threads

• Cut the threads perpendicular to the thread length, for example, with sterile curved scissors, leaving about 3 cm visible outside the cervix (Figure 9).
  
  NOTE: Cutting threads at an angle may leave sharp ends.

Figure 9. Cutting the threads

Mirena insertion is now complete.

Important information to consider during or after insertion

• If you suspect that Mirena is not in the correct position, check placement (for example, with transvaginal ultrasound). Remove Mirena if it is not positioned completely within the uterus. A removed Mirena must not be reinserted.


• If there is clinical concern and/or exceptional pain or bleeding during or after insertion, appropriate and timely measures and assessments, for example ultrasound, should be performed to exclude perforation.

Patient Counseling and Record Keeping

• Keep a copy of the consent form and lot number for your records.


• Counsel the patient on what to expect following Mirena insertion. Give the patient the Follow-up Reminder Card that is provided with the product. Discuss expected bleeding patterns during the first months of Mirena use. [See Patient Counseling Information (17.1).]


• Prescribe analgesics, if indicated.

Patient Follow-up

• Patients should be reexamined and evaluated 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

Removal of Mirena

• Remove Mirena by applying gentle traction on the threads with forceps. The arms will fold upward as it is withdrawn from the uterus. Mirena should not remain in the uterus after 5 years.


• Removal may be associated with some pain and/or bleeding or neurovascular episodes.


• If the threads are not visible and Mirena is in the uterine cavity, it may be removed using a narrow forceps, such as an alligator forceps. This may require dilation of the cervical canal [see Warnings and Precautions (5.13)].


• After removal of Mirena, verify that the system is intact.


• During difficult removals, the hormone cylinder may slide over and cover the horizontal arms. This situation generally does not require further intervention once the system is verified to be intact.


• If Mirena is removed mid-cycle and the woman has had intercourse within the preceding week, she is at a risk of pregnancy unless a new Mirena is inserted immediately following removal.

Continuation of Contraception after Removal

• You may insert a new Mirena immediately following removal.


• If a patient with regular cycles wants to start a different birth control method, remove Mirena during the first 7 days of the menstrual cycle and start the new method.


• If a patient with irregular cycles or amenorrhea wants to start a different birth control method, or if you remove Mirena after the seventh day of the menstrual cycle, start the new method at least 7 days before removal.

Dosage Forms and Strengths

Mirena is a levonorgestrel-releasing intrauterine system consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 52 mg levonorgestrel.

Contraindications

The use of Mirena is contraindicated when one or more of the following conditions exist:

• Pregnancy or suspicion of pregnancy


• Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity


• Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless there has been a subsequent intrauterine pregnancy


• Postpartum endometritis or infected abortion in the past 3 months


• Known or suspected uterine or cervical neoplasia or unresolved, abnormal Pap smear


• Genital bleeding of unknown etiology


• Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled


• Acute liver disease or liver tumor (benign or malignant)


• Conditions associated with increased susceptibility to pelvic infections


• A previously inserted IUD that has not been removed


• Hypersensitivity to any component of this product


• Known or suspected carcinoma of the breast.

Warnings and Precautions

Ectopic Pregnancy

Evaluate women who become pregnant while using Mirena for ectopic pregnancy. Up to half of pregnancies that occur with Mirena in place are ectopic. The incidence of ectopic pregnancy in clinical trials that excluded women with risk factors for ectopic pregnancy was approximately 0.1% per year.

Tell women who choose Mirena about the risks of ectopic pregnancy, including the loss of fertility. Teach them to recognize and report to their physician promptly any symptoms of ectopic pregnancy. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy.

The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Mirena is unknown. Clinical trials of Mirena excluded women with a history of ectopic pregnancy.

Intrauterine Pregnancy

If pregnancy should occur with Mirena in place, Mirena should be removed. Removal or manipulation of Mirena may result in pregnancy loss. In the event of an intrauterine pregnancy with Mirena, consider the following:

Septic abortion

In patients becoming pregnant with an IUD in place, septic abortion—with septicemia, septic shock, and death—may occur.

Continuation of pregnancy

If a woman becomes pregnant with Mirena in place and if Mirena cannot be removed or the woman chooses not to have it removed, she should be warned that failure to remove Mirena increases the risk of miscarriage, sepsis, premature labor and premature delivery. She should be followed closely and advised to report immediately any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge or leakage of fluid.

Long-term effects and congenital anomalies

When pregnancy continues with Mirena in place, long-term effects on the offspring are unknown. As of September 2006, 390 live births out of an estimated 9.9 million Mirena users had been reported. Congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the intrauterine administration of levonorgestrel and local exposure of the fetus to the hormone, the possibility of teratogenicity following exposure to Mirena cannot be completely excluded. Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Mirena is unknown.

Sepsis

As of September 2006, 9 cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena users had been reported. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Mirena is essential. GAS sepsis may also occur postpartum, after surgery, and from wounds.

Pelvic Inflammatory Disease (PID)

Mirena is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy. Use of IUDs has been associated with an increased risk of PID. The highest risk of PID occurs shortly after insertion (usually within the first 20 days thereafter) [see Warnings and Precautions (5.12)]. A decision to use Mirena must include consideration of the risks of PID.

Women at increased risk for PID

PID is often associated with a sexually transmitted disease, and Mirena does not protect against sexually transmitted disease. The risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners. Women who have had PID are at increased risk for a recurrence or re-infection.

PID warning to Mirena users

All women who choose Mirena must be informed prior to insertion about the possibility of PID and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Patients must be taught to recognize and report to their physician promptly any symptoms of pelvic inflammatory disease. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever.

Asymptomatic PID

PID may be asymptomatic but still result in tubal damage and its sequelae.

Treatment of PID

Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should be initiated promptly. Removal of Mirena after initiation of antibiotic therapy is usually appropriate. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia.

Actinomycosis has been associated with IUDs. Symptomatic women with IUDs should have the IUD removed and should receive antibiotics. However, the management of the asymptomatic carrier is controversial because actinomycetes can be found normally in the genital tract cultures in healthy women without IUDs. False positive findings of actinomycosis on Pap smears can be a problem. When possible, confirm the Pap smear diagnosis with cultures.

Irregular Bleeding and Amenorrhea

Mirena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first three to six months of Mirena use, the number of bleeding and spotting days may be increased and bleeding patterns may be irregular. Thereafter the number of bleeding and spotting days usually decreases but bleeding may remain irregular. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be taken to rule out endometrial pathology.

Amenorrhea develops in approximately 20% of Mirena users by one year. The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain [see Clinical Studies (14.1)].

In most women with heavy menstrual bleeding, the number of bleeding and spotting days may also increase during the initial months of therapy but usually decrease with continued use; the volume of blood loss per cycle progressively becomes reduced [see Clinical Studies (14.2)].

Embedment

Embedment of Mirena in the myometrium may occur. Embedment may decrease contraceptive effectiveness and result in pregnancy [see Warnings and Precautions (5.1  and5.2)]. An embedded Mirena should be removed. Embedment can result in difficult removal and, in some cases surgical removal may be necessary.

Perforation

Perforation or penetration of the uterine wall or cervix may occur during insertion although the perforation may not be detected until some time later. If perforation occurs, pregnancy may result [see Warnings and Precautions (5.1  and5.2)]. Mirena must be located and removed; surgery may be required. Delayed detection of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera.

The risk of perforation may be increased in lactating women, in women with fixed retroverted uteri, and during the postpartum period. To decrease the risk of perforation postpartum, Mirena insertion should be delayed a minimum of 6 weeks after delivery or until uterine involution is complete. If involution is substantially delayed, consider waiting until 12 weeks postpartum. Inserting Mirena immediately after first trimester abortion is not known to increase the risk of perforation, but insertion after second trimester abortion should be delayed until uterine involution is complete.

Expulsion

Partial or complete expulsion of Mirena may occur [see Warnings and Precautions (5.13)].

Symptoms of the partial or complete expulsion of any lUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it, resulting in the loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Mirena. As menstrual flow typically decreases after the first 3 to 6 months of Mirena use, an increase of menstrual flow may be indicative of an expulsion. If expulsion has occurred, Mirena may be replaced within 7 days of a menstrual period after pregnancy has been ruled out.

Ovarian Cysts

Since the contraceptive effect of Mirena is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. Sometimes atresia of the follicle is delayed and the follicle may continue to grow. Enlarged follicles have been diagnosed in about 12% of the subjects using Mirena. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously during two to three months observation. Persistent enlarged follicles should be evaluated. Surgical intervention is not usually required.

Breast Cancer

Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because breast cancer is a hormone-sensitive tumor.

Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena. Because spontaneous reports are voluntary and from a population of uncertain size, it is not possible to use postmarketing data to reliably estimate the frequency or establish causal relationship to drug exposure. Two observational studies have not provided evidence of an increased risk of breast cancer during the use of Mirena.

Patient Evaluation and Clinical Considerations

• A complete medical and social history, including that of the partner, should be obtained to determine conditions that might influence the selection of an IUD for contraception [see Contraindications (4)].


• Special attention must be given to ascertaining whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome (AIDS), I.V. drug abuse), or has a history of PID unless there has been a subsequent intrauterine pregnancy. Mirena is contraindicated in these women.


• A physical examination should include a pelvic examination, a Pap smear, examination of the breasts, and appropriate tests for any other forms of genital or other sexually transmitted diseases, such as gonorrhea and chlamydia laboratory evaluations, if indicated. Use of Mirena in patients with vaginitis or cervicitis should be postponed until proper treatment has eradicated the infection and until it has been shown that the cervicitis is not due to gonorrhea or chlamydia [see Contraindications (4)].


• Irregular bleeding may mask symptoms and signs of endometrial polyps or cancer. Because irregular bleeding/spotting is common during the first months of Mirena use, exclude endometrial pathology prior to the insertion of Mirena in women with persistent or uncharacteristic bleeding. If unexplained bleeding irregularities develop during the prolonged use of Mirena, appropriate diagnostic measures should be taken [see Warnings and Precautions (5.5)].


• The healthcare provider should determine that the patient is not pregnant. The possibility of insertion of Mirena in the presence of an existing undetermined pregnancy is reduced if insertion is performed within 7 days of the onset of a menstrual period. Mirena can be replaced by a new system at any time in the cycle. Mirena can be inserted immediately after first trimester abortion.


• Mirena should not be inserted until 6 weeks postpartum or until involution of the uterus is complete in order to reduce the incidence of perforation and expulsion. If involution is substantially delayed, consider waiting until 12 weeks postpartum [see Warnings and Precautions (5.7)].


• Patients with certain types of valvular or congenital heart disease and surgically constructed systemic-pulmonary shunts are at increased risk of infective endocarditis. Use of Mirena in these patients may represent a potential source of septic emboli. Patients with known congenital heart disease who may be at increased risk should be treated with appropriate antibiotics at the time of insertion and removal.


• Patients requiring chronic corticosteroid therapy or insulin for diabetes should be monitored with special care for infection.

Mirena should be used with caution in patients who have:

• Coagulopathy or are receiving anticoagulants


• Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia


• Exceptionally severe headache


• Marked increase of blood pressure


• Severe arterial disease such as stroke or myocardial infarction.

Insertion Precautions

• Observe strict asepsis during insertion. The presence of organisms capable of establishing PID cannot be determined by appearance, and IUD insertion may be associated with introduction of vaginal bacteria into the uterus. Administration of antibiotics may be considered, but the utility of this treatment is unknown.


• Carefully sound the uterus prior to Mirena insertion to determine the degree of patency of the endocervical canal and the internal os, and the direction and depth of the uterine cavity. In occasional cases, severe cervical stenosis may be encountered. Do not use excessive force to overcome this resistance.


• Fundal positioning of Mirena is important to prevent expulsion and maximize efficacy. Therefore, follow the instructions for the insertion carefully.


• If the patient develops decreased pulse, perspiration, or pallor, have her remain supine until these signs resolve. Insertion may be associated with some pain and/or bleeding. Syncope, bradycardia, or other neurovascular episodes may occur during insertion of Mirena, especially in patients with a predisposition to these conditions or cervical stenosis.

Continuation and Removal

• Reexamine and evaluate patients 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.


• If the threads are not visible, they may have retracted into the uterus or broken, or Mirena may have broken, perforated the uterus, or been expelled [see Warnings and Precautions (5.7 and5.8)]. If the length of the threads has changed from the length at time of insertion, the system may have become displaced. Pregnancy must be excluded and the location of Mirena verified, for example, by sonography, X-ray, or by gentle exploration of the uterine cavity with a probe. If Mirena is displaced, remove it. A new Mirena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena is in place with no evidence of perforation, no intervention is indicated.


• Promptly examine users with complaints of pain, odorous discharge, unexplained bleeding [see Warnings and Precautions (5.5)], fever, genital lesions or sores.


• Consider the possibility of ectopic pregnancy in the case of lower abdominal pain especially in association with missed periods or if an amenorrheic woman starts bleeding [see Warnings and Precautions (5.1)].

In the event a pregnancy is confirmed during Mirena use:

• Determine whether pregnancy is ectopic and, if so, take appropriate measures.


• Inform patient of the risks of leaving Mirena in place or removing it during pregnancy and of the lack of data on long-term effects on the offspring of women who have had Mirena in place during conception or gestation [see Warnings and Precautions (5.2)].


• If possible, Mirena should be removed after the patient has been warned of the risks of removal. If removal is difficult, the patient should be counseled and offered pregnancy termination.


• If Mirena is left in place, the patient's course should be followed closely.

In the event of a sexually transmitted disease during Mirena use:

Should the patient's relationship cease to be mutually monogamous, or should her partner become HIV positive, or acquire a sexually transmitted disease, she should be instructed to report this change to her clinician immediately. The use of a barrier method as a partial protection against acquiring sexually transmitted diseases should be strongly recommended. Removal of Mirena should be considered.

Mirena should be removed for the following medical reasons:

• New onset menorrhagia and/or metrorrhagia producing anemia


• Sexually transmitted disease


• Pelvic infection; endometritis


• Symptomatic genital actinomycosis


• Intractable pelvic pain


• Severe dyspareunia


• Pregnancy


• Endometrial or cervical malignancy


• Uterine or cervical perforation.

Removal of the system should also be considered if any of the following conditions arise for the first time:

• Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia


• Exceptionally severe headache


• Jaundice


• Marked increase of blood pressure


• Severe arterial disease such as stroke or myocardial infarction.

Removal may be associated with some pain and/or bleeding or neurovascular episodes.

Glucose Tolerance

Levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena.

Adverse Reactions

The following most serious adverse reactions associated with the use of Mirena are discussed in greater detail in the Warnings and Precautions section (5):

• Ectopic Pregnancy [see Warnings and Precautions (5.1)]


• Intrauterine Pregnancy [see Warnings and Precautions (5.2)]


• Group A streptococcal sepsis (GAS) [see Warnings and Precautions (5.3)]


• Pelvic Inflammatory Disease [see Warnings and Precautions (5.4)]


• Embedment [see Warnings and Precautions (5.6)]


• Perforation [see Warnings and Precautions (5.7)]


• Breast Cancer [see Warnings and Precautions (5.10)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data provided reflect the experience with the use of Mirena in the adequate and well-controlled studies for contraception (n=2,339) and heavy menstrual bleeding (n=80). For the contraception indication, Mirena was compared to a copper IUD (n=1,855), to another formulation of levonorgestrel intrauterine system (n=390) and to a combined oral contraceptive (n=94) in women 18 to 35 years old. The data cover more than 92,000 woman-months of exposure. For the treatment of heavy menstrual bleeding indication (n=80), the subjects included women aged 26 to 50 with confirmed heavy bleeding and exposed for a median of 183 treatment days of Mirena (range 7 to 295 days). The frequencies of reported adverse drug reactions represent crude incidences.

The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the contraception studies.

The most common adverse reactions (≥5% users) are uterine/vaginal bleeding alterations (51.9%), amenorrhea (23.9%), intermenstrual bleeding and spotting (23.4%), abdominal/pelvic pain (12.8%), ovarian cysts (12%), headache/migraine (7.7%), acne (7.2%), depressed/altered mood (6.4%), menorrhagia (6.3%), breast tenderness/pain (4.9%), vaginal discharge (4.9%) and IUD expulsion (4.9%).

Other relevant adverse reactions occurring in <5% of subjects include nausea, nervousness, vulvovaginitis, dysmenorrhea, back pain, weight increase, decreased libido, cervicitis/Papanicolaou smear normal/class II, hypertension, dyspareunia, anemia, alopecia, skin disorders including eczema, pruritus, rash and urticaria, abdominal distention, hirsutism and edema.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Mirena: device breakage and angioedema. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions

Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the serum concentrations of progestins.

Some drugs or herbal products that may decrease the serum concentration of levonorgestrel include:

• barbiturates


• bosentan


• carbamazepine


• felbamate


• griseofulvin


• oxcarbazepine


• phenytoin


• rifampin


• St. John’s wort


• topiramate.

Significant changes (increase or decrease) in the serum concentrations of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Consult the labeling of all concurrently used drugs to obtain further information about interactions with Mirena or the potential for enzyme alterations.

USE IN SPECIFIC POPULATIONS

Pregnancy

Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects. [Also see Contraindications (4), Warnings and Precautions (5.1 and 5.2).]

Nursing Mothers

In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant serum. [Also,see Warnings and Precautions (5.7 ).]

Pediatric Use

Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatric Use

Mirena has not been studied in women over age 65 and is not currently approved for use in this population.

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel released from Mirena [see Contraindications (4)].

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel released from Mirena.

Mirena Description

Mirena is intended to provide an initial release rate of 20 mcg/day of levonorgestrel

Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2, and the following structural formula:

Mirena

Mirena (levonorgestrel-releasing intrauterine system) consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The reservoir consists of a white or almost white cylinder, made of a mixture of levonorgestrel and silicone (polydimethylsiloxane), containing a total of 52 mg levonorgestrel. The reservoir is covered by a semi-opaque silicone (polydimethylsiloxane) membrane. The T-body is 32 mm in both the horizontal and vertical directions. The polyethylene of the T-body is compounded with barium sulfate, which makes it radiopaque. A monofilament brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the T-body.

Schematic drawing of Mirena

Inserter

Mirena is packaged sterile within an inserter. The inserter, which is used for insertion of Mirena into the uterine cavity, consists of a symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. Once Mirena is in place, the inserter is discarded.

Diagram of Inserter

Mirena - Clinical Pharmacology

Mechanism of Action

The local mechanism by which continuously released levonorgestrel enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.

Pharmacodynamics

Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of levonorgestrel1 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.

Ovulation is inhibited in some women using Mirena. In a 1-year study approximately 45% of menstrual cycles were ovulatory and in another study after 4 years 75% of cycles were ovulatory.

Pharmacokinetics

Absorption

Low doses of levonorgestrel are administered into the uterine cavity with the Mirena intrauterine delivery system. Initially, levonorgestrel is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years. A stable serum concentration, without peaks and troughs, of levonorgestrel of 150–200 pg/mL occurs after the first few weeks following insertion of Mirena. Levonorgestrel concentrations after long-term use of 12, 24, and 60 months were 180±66 pg/mL, 192±140 pg/mL, and 159±59 pg/mL, respectively.

Distribution

The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β- tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in levonorgestrel concentrations seen in individuals using levonorgestrel–containing contraceptive products.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of levonorgestrel after daily oral doses is approximately 17 hours.

Specific Populations

Pediatric: Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatric: Mirena has not been studied in women over age 65 and is not currently approved for use in this population.

Race: No studies have evaluated the effect of race on pharmacokinetics of Mirena.

Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Mirena.

Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mirena.

Drug-Drug Interactions

No drug-drug interaction studies were conducted with Mirena [see Drug Interactions (7)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Long-term studies in animals to assess the carcinogenic potential of levonorgestrel releasing intrauterine system have not been performed. There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorigenicity following parenteral administration of levonorgestrel to rats for 2 years at approximately 5 mcg/day, or following oral administration to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 mcg/kg/day. In another 7 year dog study, oral administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies. The nonclinical doses above are respectively 16, 200, 240 and 810 times t