Mutamycin

Generic Name: Mitomycin
Class: Antineoplastic Agents
VA Class: AN200
Molecular Formula: C₁₅H₁₈N₄O₅
CAS Number: 50-07-7

• Experience of Supervising Clinician


• 
  

  Administer only under the supervision of a qualified clinician experienced in therapy with chemotherapeutic agents.^{100 d} Use only when adequate treatment facilities for appropriate management of therapy and complications are available.^{100 d} (See Toxicity under Cautions.)

  
  

• Myelosuppression


• 
  

  Risk of dose-limiting, cumulative myelosuppression and potentially life-threatening secondary infections (e.g., septicemia).^{100 c d} (See Hematologic Effects under Cautions.)

  
  

• Hemolytic Uremic Syndrome


• 
  

  Undefined risk of severe and often fatal syndrome consisting principally of microangiopathic hemolytic anemia (hematocrit ≤25%), thrombocytopenia (platelet count ≤100,000/mm³), and irreversible renal failure (S_cr ≥1.6 mg/dL).^{100 101 102 103 104 105 106 107 108 d} (See Hemolytic Uremic Syndrome under Cautions.)

  
  


• 
  

  May occur at any time during therapy (with or without other antineoplastic agents); however, most cases occur at mitomycin doses ≥60 mg.^{100 d} Blood transfusion may exacerbate the symptoms associated with this syndrome.^{100 d}

  
  

Introduction

Antineoplastic agent; an antibiotic produced by Streptomyces caespitosus.^{100 c d}

Uses for Mutamycin

Adenocarcinoma of Stomach and Pancreas

Component of combination chemotherapeutic regimens for treatment of disseminated adenocarcinoma of the stomach or pancreas and as palliative treatment of these tumors when other treatment modalities are ineffective.^{100 121 d}

Response rates generally low (10–17%) and of short duration.^c

Not recommended for use as single-agent, primary therapy or as a replacement for appropriate surgery and/or radiation therapy.^{100 d}

Anal Cancer

A preferred regimen, in combination with fluorouracil, for primary treatment of anal cancer†.¹²¹

Bladder Cancer

Has been used for intravesical† treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder cancer†.^{113 115 120 121 130 131 138}

Causes regression of existing papillary tumor and reduces the rate of short-term tumor recurrence but has no effect on disease progression or overall survival.^{119 123 124 129 139}

Cervical Cancer

Has been used in cisplatin-containing combination chemotherapy regimens (e.g., bleomycin, cisplatin, mitomycin, and vincristine) for treatment of metastatic or recurrent cervical cancer†.^{132 135}

Other agents generally preferred for treatment of advanced cervical cancer†.^{136 137}

Non-small Cell Lung Cancer

Has been used for treatment of non-small cell lung cancer† in combination with cisplatin and vinblastine (MVP) ^{121 146 149} or ifosfamide with mesna (MIC).^{121 150}

Other chemotherapeutic regimens (e.g., cisplatin with paclitaxel, vinorelbine, or gemcitabine) currently preferred for treatment of advanced non-small cell lung cancer†.^{121 146}

Malignant Mesothelioma

Has been used for treatment of malignant mesothelioma†.¹²¹

Head and Neck Carcinoma

Has been used as an adjunct to radiation therapy for treatment of squamous cell carcinoma of head and neck†.¹⁴⁷

Breast Cancer

Has shown activity for treatment of metastatic breast cancer†.¹⁴⁸

Mutamycin Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.^{100 d}

  
  


• 
  

  Administer mitomycin only after complete hematologic recovery from any previous chemotherapy occurs.¹⁰⁰

  
  

Administration

Administer IV.^{100 c d}

Has been administered intravesically†; not an approved route of administration.^{100 115 120 121 130 131 138 d}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer via a functioning IV catheter;^{100 c d} some clinicians recommend administering the drug through tubing of an IV infusion.^c Use care to avoid extravasation.^{100 d} (See Mucocutaneous Effects under Cautions.)

Reconstitution

Reconstitute vial containing 5, 20, or 40 mg of mitomycin with 10, 40, or 80 mL of sterile water for injection, respectively, to provide a solution containing approximately 0.5 mg/mL.^{100 c d}

Shake vial to dissolve.^{100 c d} If the powder does not dissolve immediately, allow the vial to stand at room temperature until complete dissolution occurs.^{100 c d}

Dosage

Consult published protocols for dosages of mitomycin and other chemotherapeutic agents and the method and sequence of administration.^c

Individualize dosage based on clinical and hematologic response and tolerance of the patient and whether or not other myelosuppressive therapy also is being used.^{100 c d}

Reevaluate patients after each course of therapy and adjust dosages as needed.^{100 d}

Adults

Adenocarcinoma of Stomach and Pancreas

IV

Initially, 20 mg/m² as a single IV dose every 6–8 weeks.^{100 d} Doses >20 mg/m² are not more effective and increase risk of toxicity.^{100 d}

Adjust subsequent dosages according to the hematologic response to the previous dose.^{100 d} (See Table 1.) Do not administer repeat dosage until leukocyte count has returned to 4000/mm³ and platelet count to 100,000/mm³.^{100 d}

Table 1: Dosage Modification for Myelosuppression Based on Nadir After Prior Dose100d

Leukocytes (cells/ mm3)	Platelets (cells/ mm3)	Percentage of Prior Dose to Be Given
>4000	>100,000	100%
3000–3999	75,000–99,999	100%
2000–2999	25,000–74,999	70%
<2000	<25,000	50%

If disease continues to progress after 2 courses of therapy, discontinue the drug since likelihood of response is minimal.^{100 d}

Bladder Cancer†

Treatment of Superficial Bladder Cancer†

Intravesical†

Usual dosage: 20–60 mg once weekly,^{115 116 118 120 125 126 127 128} administered as soon as possible following transurethral resection (TUR).^{117 128} For patients treated within 6–24 hours following TUR, a 6-month course of therapy generally is sufficient; however, for patients in whom intravesical therapy is instituted ≥24 hours following surgery, a 12-month course usually is recommended.^{117 128} No additional benefit demonstrated for continued maintenance therapy.^{115 116 120 124 128 131}

Special Populations

Hepatic Impairment

No special dosage recommendations at this time.^{100 d}

Renal Impairment

Do not administer if S_cr >1.7 mg/dL.^{100 d} (See Renal Effects under Cautions.)

Geriatric Patients

No special dosage recommendations at this time.^{100 d}

Cautions for Mutamycin

Contraindications

• 
  

  Thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes.^{100 c d} (See Hematologic Effects under Cautions.)

  
  


• 
  

  Known hypersensitivity or idiosyncratic reaction to mitomycin.^{100 c d}

  
  

Warnings/Precautions

Warnings

Toxicity

Highly toxic drug with a low therapeutic index.^c Administer only under the supervision of a qualified clinician experienced in use of cancer chemotherapeutic agents.^{100 c d} (See Boxed Warning and also see Hematologic Effects, Renal Effects, Hemolytic Uremic Syndrome, and Respiratory Effects under Cautions.)

Hematologic Effects

High incidence of cumulative myelosuppression, principally thrombocytopenia and leukopenia.^{100 c d} (See Boxed Warning.) Not related to total dose; however, occurs more frequently with certain dosage regimens.^c

Monitor hematologic status (platelet count, leukocyte count, differential, PT, bleeding time, and hemoglobin) repeatedly during therapy and for ≥8 weeks afterwards.^{100 c d} Withhold therapy if leukocyte count <4000/mm³, platelet count <100,000/mm³, or if a progressive decline in either occurs.^{100 d} (See Table 1.)

Myelosuppression may occur anytime within 8 weeks after initiation of therapy; may be severe (e.g., platelet count ≤50,000/mm³, leukocyte count ≤2000/mm³).^{100 c d} Nadir during 4–6 weeks of therapy.^c Recovery usually occurs ≤10 weeks after therapy discontinued; however, about 25% of cases may be irreversible.^{100 d}

Hemorrhagic Complications

Bleeding due to thrombocytopenia may occur.^c Platelet transfusions may be needed.^c

Infectious Complications

Life-threatening infections secondary to leukopenia (e.g., septicemia) reported.^{100 c d}

Renal Effects

Renal toxicity (e.g., increased BUN and/or S_cr) reported.^{100 c d} Possibly related to total dose administered (e.g., low risk at cumulative doses <50 mg/m²; substantially increases with higher cumulative doses);^{101 108} however, not clearly established.^{100 d}

Monitor renal function.¹⁰⁰ Do not administer if S_cr >1.7 mg/dL.^{100 d}

Renal failure also may occur as a component of hemolytic uremic syndrome.^{100 101 102 103 104 105 106 107 108} (See Hemolytic Uremic Syndrome under Cautions and also see Boxed Warning.)

Fetal/Neonatal Morbidity

May cause fetal harm; teratogenicity demonstrated in animals.^{100 d}

Safe use of mitomycin in pregnant women not established.^{100 d}

Major Toxicities

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome, a severe and often fatal syndrome of microangiopathic hemolytic anemia (hematocrit ≤25%), thrombocytopenia (platelet count ≤100,000/mm³), and irreversible renal failure (S_cr ≥1.6 mg/dL), reported.^{100 101 102 103 104 105 106 107 108 d} Pulmonary edema also may be a component; may be a particularly grave prognostic factor.^{100 104 d} Other complications include neurologic abnormalities and hypertension.^{100 d} (See Boxed Warning.)

Syndrome can vary from a chronic course with mild anemia and slowly progressive renal impairment to a fulminant course with severe anemia, rapid deterioration of renal function, and death.^{101 102 103 104 105 106 107 108}

May occur at any time during therapy (with or without other antineoplastic agents); however, most cases occur at doses ≥60 mg.^{100 d} Blood transfusion may exacerbate symptoms.^{100 d}

Closely monitor patients receiving mitomycin doses ≥60 mg for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function.^{100 d}

Optimum management of syndrome not established; use of systemic corticosteroids, plasma exchange, plasmapheresis, and/or IV vincristine beneficial in some patients, and early treatment may be preferred.^{103 104 105 106 107 108} (See Specific Drugs under Interactions.) Manufacturer states that therapy for syndrome is investigational.^{100 d}

General Precautions

Mucocutaneous Effects

Extremely irritating to tissues.^c Mucocutaneous toxicity (e.g., mouth ulcers, alopecia, desquamation, pruritus) may occur; appears related to the total dose given.^{c d}

Extravasation possible; may cause severe cellulitis, ulceration, and tissue sloughing.^{100 d} May occur with or without symptoms (e.g., stinging or burning during administration) and even when blood returns well during initial aspiration of infusion needle.^{100 d} (See IV Administration under Dosage and Administration.)

Possible pain on injection, induration, thrombophlebitis, and paresthesia.^c Delayed erythema and/or ulceration at or distant from the injection site possible weeks to months after administration despite the lack of apparent evidence of extravasation.^{100 d}

Respiratory Effects

Possibly severe or life-threatening acute bronchospasm and/or dyspnea may occur a few minutes to several hours after administration of a vinca alkaloid (e.g., vinblastine) in patients who have been previously or simultaneously treated with mitomycin.^{100 c d} Bronchodilators, corticosteroids, and/or oxygen may produce symptomatic relief.^{100 d}

ARDS reported in some patients receiving mitomycin in combination with other antineoplastic agents and maintained at fraction of inspired oxygen (FIO₂) concentrations >50% perioperatively.^{100 d} Use only enough oxygen to provide adequate arterial saturation.^{100 d}

Monitor patients for evidence of pulmonary toxicity (e.g., dyspnea with a nonproductive cough, radiographic evidence of pulmonary infiltrates) and for changes in fluid balance; avoid overhydration.^{100 d} If pulmonary toxicity develops, discontinue therapy if other etiologies can be excluded.^{100 d}

Intravesical Instillation

Bladder fibrosis/contraction reported;^{100 d} may require cystectomy.^{100 d}

Asymptomatic ulcers at the site of resected carcinoma of the bladder^{109 110 111} and calcification of bladder wall reported.¹¹²

Possible local irritation (i.e., cystitis); local toxicity increases with the number and frequency of instillations and with the dose administered.¹¹⁵

GI Effects

Nausea and vomiting may occur within 1–2 hours of IV administration.^{100 c d} Vomiting usually subsides rapidly but nausea can continue for 2–3 days.^c

Specific Populations

Pregnancy

Category C.^{100 d} (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Not known whether mitomycin is distributed into milk.^{100 d} Discontinue nursing during mitomycin therapy.^{100 d}

Pediatric Use

Safety and efficacy not established.^{100 d}

Renal Impairment

Do not use if S_cr >1.7 mg/dL.^{100 d} Monitor renal function prior to and periodically during therapy.^{100 d} (See Renal Effects under Cautions.)

Common Adverse Effects

IV administration: Myelosuppression, nausea, vomiting, anorexia, stomatitis, fever, alopecia.^{100 d}

Intravesical† instillation: Local irritation (i.e., cystitis).¹¹⁵

Interactions for Mutamycin

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents	Risk of acute pulmonary reactions following administration of vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine) in patients previously or concomitantly treated with mitomycin100 d (see Respiratory Effects under Cautions) Risk of ARDS in patients receiving mitomycin in combination with other chemotherapeutic agents and oxygen therapy100 c d (see Respiratory Effects under Cautions)	Bronchodilators, corticosteroids, and/or oxygen may produce symptomatic relief from acute bronchospasm and/or dyspnea100 d Use only enough oxygen to provide adequate arterial saturation during ARDS100 d
Myelosuppressive agents		Adjust dosages accordingly when used concomitantly100 d

Mutamycin Pharmacokinetics

Distribution

Extent

Rapidly distributed into tissues.^c

In animals, highest concentrations found in the kidneys, followed by muscles, eyes, lungs, intestines, and stomach; not detectable in the liver, spleen, or brain (rapidly inactivate mitomycin).^c

Higher concentrations of the drug are generally present in cancer tissues than in normal tissues.^c

Not known whether mitomycin is distributed into milk.^{100 d}

Elimination

Metabolism

Rapidly inactivated in microsomal fraction of the liver and also in the kidneys, spleen, brain, and heart, which contain high concentrations of enzymes capable of metabolizing the drug.^{100 c}

Elimination Route

Excreted principally in urine (about 10% as active drug) and to a small extent in bile.^{100 c d}

Rate of clearance inversely proportional to the maximum serum concentration because of saturation of degradative pathways.^{100 d}

Half-life

For 30-mg IV injection: 17 minutes.^{100 d}

Stability

Storage

Parenteral

Powder for Injection

15–30°C.^{c d} Protect from light^c and avoid excessive heat (>40°C).^{100 c d} Commercially available mitomycin powder is stable for at least 4 years at room temperature.^c

Reconstituted solutions are stable for 7 days at room temperature and for 14 days at 2–8°C.^{100 c d} Protect from light.^d

Compatibility

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

Parenteral

Solution Compatibility^{100 a}

Solutions of mitomycin diluted to a concentration of 20–40 mcg/mL are stable at room temperature for 3 hours in 5% dextrose injection, 12 hours in 0.9% sodium chloride, and 24 hours in sodium lactate injection.^{100 c d}

Compatible
Ringer’s injection, lactated
Sodium chloride 0.4 or 0.6%
Incompatible
Dextrose 3.3% in sodium chloride 0.3%
Variable
Dextrose 5%
Dextrose 5% in water
Sodium chloride 0.9%
Sodium lactate

Drug Compatibility

The combination of mitomycin 5–15 mg and heparin 1000–10,000 units in 30 mL of 0.9% sodium chloride injection is stable for 48 hours at room temperature.^{100 d}

Admixture Compatibilitya

Compatible
Dexamethasone sodium phosphate
Hydrocortisone sodium succinate
Incompatible
Bleomycin sulfate
Variable
Heparin sodium

Y-Site Compatibilitya

Compatible
Amifostine
Bleomycin sulfate
Cisplatin
Cyclophosphamide
Doxorubicin HCl
Droperidol
Fluorouracil
Furosemide
Granisetron HCl
Heparin sodium
Leucovorin calcium
Melphalan HCl
Methotrexate sodium
Metoclopramide HCl
Ondansetron HCl
Teniposide
Thiotepa
Vinblastine sulfate
Vincristine sulfate
Incompatible
Aztreonam
Cefepime HCl
Etoposide phosphate
Filgrastim
Gemcitabine HCl
Piperacillin sodium–tazobactam sodium
Sargramostim
Topotecan HCl
Vinorelbine tartrate

Actions and SpectrumActions

• 
  

  Mechanism of antineoplastic activity similar to that of other alkylating agents.^c

  
  


• 
  

  Enzymatic reduction of mitomycin within susceptible cells may be necessary for antineoplastic activity.^c

  
  


• 
  

  Activated mitomycin appears to selectively inhibit the synthesis of deoxyribonucleic acid (DNA) by causing cross-linking of DNA.^{100 c d} In high concentrations, may also inhibit RNA and protein synthesis.^{100 d}

  
  


• 
  

  Active against gram-positive bacteria and some viruses; however cytotoxicity precludes use as an anti-infective agent.^c

  
  

Advice to Patients

• 
  

  Importance of advising patients of potentially life-threatening hematologic (e.g., myelosuppression), respiratory, and renal toxicities associated with mitomycin therapy.^{100 c d}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{100 d}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., bleeding disorders).^{100 d}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{100 d} (See Cautions.)

  
  

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Mitomycin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection	5 mg*	Mitomycin for Injection
			Mutamycin	Bristol-Myers Squibb
		20 mg*	Mitomycin for Injection
			Mutamycin	Bristol-Myers Squibb
		40 mg	Mitomycin for Injection
			Mutamycin	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 June 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

Only references cited for selected revisions after 1984 are available electronically.

100. Bristol-Myers Squibb. Mutamycin (mitomycin for injection) prescribing information. Princeton, NJ; 2000 Jan.

101. Valavaara R, Nordman E. Renal complications of mitomycin C therapy with special reference to the total dose. Cancer. 1985; 55:47-50. [IDIS 194940] [PubMed 3917353]

102. Pavy MD, Wiley EL, Abeloff MD. Hemolytic-uremic syndrome associated with mitomycin therapy. Cancer Treat Rep. 1982; 66:457-61. [IDIS 148370] [PubMed 7060035]

103. Rabadi SJ, Khandekar JD, Miller HJ. Mitomycin-induced hemolytic uremic syndrome: case presentation and review of literature. Cancer Treat Rep. 1982; 66:1244-7. [IDIS 151626] [PubMed 7083229]

104. Sheldon R, Slaughter D. A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma. Cancer. 1986; 58:1428-36. [IDIS 221489] [PubMed 3091244]

105. Price TM, Murgo AJ, Keveney JJ et al. Renal failure and hemolytic anemia associated with mitomycin C: a case report. Cancer. 1985; 55:51-6. [IDIS 194941] [PubMed 3917354]

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126. Witjes JA, Meijden APM, Witjes WPJ et al. A randomised prospective study comparing intravesical instillations of mitomycin-C, BCG-Tice, and BCG-RIVM in pTa-pT1 tumours and primary carcinoma in situ of the urinary bladder. Eur J Cancer. 1993; 29A:1672-6. [PubMed 8398292]

127. Krege S, Giani G, Meyer R et al. A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guerin. J Urol. 1996; 156:962-6. [IDIS 372561] [PubMed 8709374]

128. Bouffioux C, Kurth KH, Bono A et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. J Urol. 1995; 153:934-41. [IDIS 342231] [PubMed 7853578]

129. Pawinski A, Sylvester R, Kurth KH et al. A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. J Urol. 1996; 156:1934-41. [IDIS 376162] [PubMed 8911360]

130. Bouffioux C, van der Meijden A, Kurth KH et al. Objective response of superficial bladder tumors to intravesical treatment (including review of response of marker lesions). Prog Clin Biol Res. 1992; 378:29-42. [PubMed 1301584]

131. Akaza H, Isaka S, Koiso K et al. Comparative analysis of short-term and long-term prophylactic intravesical chemotherapy of superficial bladder cancer. Cancer Chemother Pharmacol. 1987; 20(Suppl):S91-6.

132. Shimizu Y, Akiyama F, Umezawa S et al. Combination of consecutive low-dose cisplatin with bleomycin, vincristine, and mitomycin for recurrent cervical carcinoma. J Clin Oncol. 1998; 16:1869-78. [IDIS 406129] [PubMed 9586903]

133. Omura GA, Blessing JA, Vaccarello L et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997; 15:165-71. [IDIS 379607] [PubMed 8996138]

134. Kumar L, Pokharel YH, Kumar S et al. Single agent versus combination chemotherapy in recurrent cervical cancer. J Obstet Gynaecol Res. 1998; 24:401-9. [PubMed 10063235]

135. Alberts DS, Kronmal R, Baker LH et al. Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol. 1987; 5:1791-5. [PubMed 2445932]

136. Thigpen T, Blessing JA, Gallup DG et al. Phase II trial of mitomycin-C in squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1995; 57:376-9. [PubMed 7774841]

137. Reviewers’ comments (personal observations) on cervical cancer.

138. Heney NM, Koontz WW, Barton B et al. Intravesical thiotepa versus mitomycin C in patients with Ta, T1 and TIS transitional cell carcinoma of the bladder: a phase III prospective randomized study. J Urol. 1988; 140:1390-3. [IDIS 249229] [PubMed 3143016]

139. Smith JA Jr, Labasky RF, Cockett ATK et al. Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). The American Urological Association. J Urol. 1999; 162:1697-701. [IDIS 437182] [PubMed 10524909]

140. Herr HW, Schwalb DM, Zhang ZF et al. Intravesical Bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol. 1995; 13:1404-8. [IDIS 348856] [PubMed 7751885]

141. De Jager R, Guinan P, Lamm D et al. Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette-Guerin: overview analysis of six phase II clinical trials. Urology. 1991; 38:507-13. [PubMed 1836081]

142. Sarosdy MF, Lamm DL. Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol. 1989; 142:719-22. [IDIS 265265] [PubMed 2769847]

143. Malmstrom PU, Wijkstrom H, Lundholm C et al. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol. 1999; 161:1124-7. [IDIS 426475] [PubMed 10081852]

144. Ali-el-Dein B, Nabeeh A, el-Baz M et al. Single-dose versus multiple instillations of epirubicin as prophylaxis for recurrence after transurethral resection of pTa and pT1 transitional-cell bladder tumours: a prospective, randomized controlled study. Br J Urol. 1997; 79:731-5. [PubMed 9158511]

145. Okamura K, Kinukawa T, Tsumura Y et al. A randomized study of short- versus long-term intravesical epirubicin instillation for superficial bladder cancer. Nagoya University Urological Oncology Group. Eur Urol. 1998; 33:285-9. [PubMed 9555553]

146. Non-small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 May 22.

147. Haffty BG, Son YH, Papac R et al. Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials. J Clin Oncol. 1997; 15:268-76. [IDIS 379619] [PubMed 8996152]

148. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Apr 3.

149. Veeder MH, Jett JR, Su JQ et al. A phase III trial of mitomycin C alone versus mitomycin C, vinblastine, and cisplatin for metastatic squamous cell lung carcinoma. Cancer. 1992; 70:2281-7. [IDIS 304727] [PubMed 1394057]

150. Crino L, Scagliotti GV, Ricci S et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol. 1999; 17:3522-30. [IDIS 437734] [PubMed 10550150]

152. UKCCCR Anal Cancer Trial Working Party, UK Co-ordinating Committee on Cancer Research. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996; 348:1049-54. [PubMed 8874455]

153. Bartelink H, Roelofsen F, Eschwege F et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal ca

CureChrome Solution

Pronunciation: ben-zal-KOE-nee-um
Generic Name: Benzalkonium Chloride
Brand Name: CureChrome

CureChrome Solution is used for:

Treating minor cuts, scrapes, and burns.

CureChrome Solution is a topical antiseptic. It works by preventing infection.

Do NOT use CureChrome Solution if:

• you are allergic to any ingredient in CureChrome Solution


• you have a deep puncture wound, animal bite, or serious burn

Contact your doctor or health care provider right away if any of these apply to you.

Before using CureChrome Solution:

Some medical conditions may interact with CureChrome Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with CureChrome Solution. However, no specific interactions are known at this time.

Ask your health care provider if CureChrome Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use CureChrome Solution:

Use CureChrome Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• CureChrome Solution is for external use only. Do not use in or near the eyes or apply to large parts of the body.


• Wash your hands before and after using CureChrome Solution, unless your hands are part of the treated area.


• Clean the affected area before applying CureChrome Solution.


• Apply a small amount of CureChrome Solution to the affected area up to 3 times daily, or as directed by your doctor.


• Do not apply CureChrome Solution to blistered skin.


• You may use a sterile bandage to cover the treated area. Allow the treated area to dry first.


• If you miss a dose of CureChrome Solution, use it as soon as you remember. Continue to use it as directed by your doctor or on the package label.

Ask your health care provider any questions you may have about how to use CureChrome Solution.

Important safety information:

• CureChrome Solution is for external use only. Do not get it in your eyes, nose, or mouth. If you get it in your eyes, rinse right away with cool tap water.


• If you use topical products too often, your condition may become worse.


• Do NOT use more than the recommended dose or use for longer than 1 week without checking with your doctor.


• Check with your doctor before using CureChrome Solution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using CureChrome Solution while you are pregnant. It is not known if CureChrome Solution is found in breast milk after topical use. If you are or will be breast-feeding while you use CureChrome Solution, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of CureChrome Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Minor irritation at the application site.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); infection; severe or persistent irritation, redness, pain, or swelling.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: CureChrome side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of CureChrome Solution:

Store CureChrome Solution at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Do not freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Keep CureChrome Solution out of the reach of children and away from pets.

General information:

• If you have any questions about CureChrome Solution, please talk with your doctor, pharmacist, or other health care provider.


• CureChrome Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about CureChrome Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More CureChrome resources

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

Compare CureChrome with other medications

• Bacterial Skin Infection

Levorphanol

Dosage Form: tablet
Levorphanol TARTRATE TABLETS USP, 2 mg, CII

Rx only

Levorphanol Description

Levorphanol tartrate is a potent opioid analgesic with a molecular formula of C17H23NO • C4H6O6 • 2H2O and molecular weight 443.5. Each mg of Levorphanol tartrate is equivalent to 0.58 mg Levorphanol base. Levorphanol’s chemical name is levo-3-hydroxy-N-methylmorphinan. The USP nomenclature is 17-methylmorphinan 3-ol tartrate (1:1)(Salt) dihydrate. The material has 3 asymmetric carbon atoms. The chemical structure is:

Levorphanol tartrate is a white crystalline powder, soluble in water and ether but insoluble in chloroform.

Each tablet, for oral administration, contains 2 mg Levorphanol tartrate. In addition, each tablet contains anhydrous lactose, corn starch, and magnesium stearate.

Levorphanol - Clinical Pharmacology

Pharmacodynamics

Levorphanol is a potent synthetic opioid similar to morphine in its actions. Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain. Onset of analgesia and peak analgesic effect following administration of Levorphanol are similar to morphine when administered at equianalgesic doses.

Levorphanol produces a degree of respiratory depression similar to that produced by morphine at equianalgesic doses, and like many mu-opioid drugs, Levorphanol produces euphoria or has a positive effect on mood in many individuals.

As with other opioids, the blood levels required for analgesia are determined by the opioid tolerance of the patient, and are likely to rise with chronic use. The rate of development of tolerance is highly variable, and is determined by the dose, dosing interval, age, use of concomitant drugs and physical status of the patient. While blood levels of opioid drugs may be helpful in assessing individual cases, dosage is usually adjusted by careful clinical observation of the patient.

Pharmacokinetics

The pharmacokinetics of Levorphanol have been studied in a limited number of cancer patients following intravenous (IV), intramuscular (IM) and oral (PO) administration. Following IV administration plasma concentrations of Levorphanol decline in a triexponential manner with a terminal half-life of 11 to 16 hours and a clearance of 0.78 to 1.1 L/kg/hr. Based on terminal half-life, steady-state plasma concentrations should be achieved by the third day of dosing. Levorphanol is rapidly distributed (<1 hr) and redistributed (1 to 2 hours) following IV administration and has a steady-state volume of distribution of 10 to 13 L/kg. In vitro studies of protein binding indicate that Levorphanol is only 40% bound to plasma proteins.

No pharmacokinetic studies of the absorption of IM Levorphanol are available, but clinical data suggests that absorption is rapid with onset of effects within 15 to 30 minutes of administration.

Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing. The bioavailability of Levorphanol tablets compared to IM or IV administration is not known.

Plasma concentrations of Levorphanol following chronic administration in patients with cancer increased with the dose, but the analgesic effect was dependent on the degree of opioid tolerance of the patient. Expected steady-state plasma concentrations for a 6-hour dosing interval can reach 2 to 5 times those following a single dose, depending on the patient’s individual clearance of the drug. Very high plasma concentrations of Levorphanol can be reached in patients on chronic therapy due to the long half-life of the drug. One study in 11 patients using the drug for control of cancer pain reported plasma concentrations from 5 to 10 ng/mL after a single 2 mg dose and up to 50 to 100 ng/mL after repeated oral doses of 20 to 50 mg/day.

Animal studies suggest that Levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. This renally excreted inactive glucuronide metabolite accumulates with chronic dosing in plasma at concentrations that reach fivefold that of the parent compound.

The effects of age, gender, hepatic and renal disease on the pharmacokinetics of Levorphanol are not known. As with all drugs of this class, patients at the extremes of age are expected to be more susceptible to adverse effects because of a greater pharmacodynamic sensitivity and probable increased variability in pharmacokinetics due to age or disease.

Clinical Trials

Clinical trials have been reported in the medical literature that investigated the use of Levorphanol as a preoperative medication, as a postoperative analgesic, and in the management of chronic pain due primarily to malignancy. In each of these clinical settings Levorphanol has been shown to be an effective analgesic of the mu-opioid type and similar to morphine, meperidine, or fentanyl.

Levorphanol has been studied in chronic cancer patients. Dosages were individualized to each patient’s level of opioid tolerance. In one study, starting doses of 2 mg twice a day often had to be advanced by 50% or more within a few weeks of starting therapy. A study of Levorphanol indicates that the relative potency is approximately 4 to 8 times that of morphine, depending on the specific circumstances of use. In postoperative patients, intramuscular Levorphanol was determined to be about 8 times as potent as intramuscular morphine, whereas in cancer patients with chronic pain, it was found to be only about 4 times as potent.

INDIVIDUALIZATION OF DOSAGE

Accepted medical practice dictates that the dose of any opioid analgesic be appropriate to the degree of pain to be relieved, the clinical setting, the physical condition of the patient, and the kind and dose of concurrent medication.

Levorphanol has a long half-life similar to methadone or other slowly excreted opioids, rather than quickly excreted agents such as morphine or meperidine. Slowly excreted drugs may have some advantages in the management of chronic pain. Unfortunately, the duration of pain relief after a single dose of a slowly excreted opioid cannot always be predicted from pharmacokinetic principles, and the inter-dose interval may have to be adjusted to suit the patient’s individual pharmacodynamic response.

Levorphanol is 4 to 8 times as potent as morphine and has a longer half-life. Because there is incomplete cross-tolerance among opioids, when converting a patient from morphine to Levorphanol, the total daily dose of oral Levorphanol should begin at approximately 1/15 to 1/12 of the total daily dose of oral morphine that such patients had previously required and then the dose should be adjusted to the patient’s clinical response. If a patient is to be placed on fixed-schedule dosing (round-the-clock) with this drug, care should be taken to allow adequate time after each dose change (approximately 72 hours) for the patient to reach a new steady-state before a subsequent dose adjustment to avoid excessive sedation due to drug accumulation.

Indications and Usage for Levorphanol

Levorphanol Tartrate Tablets USP are indicated for the management of moderate to severe pain where an opioid analgesic is appropriate.

Contraindications

Levorphanol Tartrate Tablets USP are contraindicated in patients hypersensitive to Levorphanol tartrate.

Warnings

Respiratory Depression

Levorphanol, like morphine, may be expected to produce serious or potentially fatal respiratory depression if given in an excessive dose, too frequently, or if given in full dosage to compromised or vulnerable patients. This is because the doses required to produce analgesia in the general clinical population may cause serious respiratory depression in vulnerable patients. Safe usage of this potent opioid requires that the dose and dosage interval be individualized to each patient based on the severity of the pain, weight, age, diagnosis and physical status of the patient, and the kind and dose of concurrently administered medication.

The initial dose of Levorphanol should be reduced by 50% or more when the drug is given to patients with any condition affecting respiratory reserve or in conjunction with other drugs affecting the respiratory center. Subsequent doses should then be individually titrated according to the patient’s response. Respiratory depression produced by Levorphanol tartrate can be reversed by naloxone, a specific antagonist (see OVERDOSAGE).

Preexisting Pulmonary Disease

Because Levorphanol causes respiratory depression, it should be administered with caution to patients with impaired respiratory reserve or respiratory depression from some other cause (e.g., from other medication, uremia, severe infection, obstructive respiratory conditions, restrictive respiratory diseases, intrapulmonary shunting or chronic bronchial asthma). As with other strong opioids, use of Levorphanol in acute or severe bronchial asthma is not recommended (see Respiratory Depression).

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of Levorphanol with carbon dioxide retention and secondary elevation of cerebral spinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or pre-existing increase in intracranial pressure. Opioids, including Levorphanol, produce effects that may obscure neurological signs of further increase in pressure in patients with head injuries. In addition, Levorphanol may affect level of consciousness that may complicate neurological evaluation.

Cardiovascular Effects

The use of Levorphanol in acute myocardial infarction or in cardiac patients with myocardial dysfunction or coronary insufficiency should be limited because the effects of Levorphanol on the work of the heart are unknown.

Hypotensive Effect

The administration of Levorphanol may result in severe hypotension in the postoperative patient or in any individual whose ability to maintain blood pressure has been compromised by a depleted blood volume or by administration of drugs, such as phenothiazines or general anesthetics. Opioids may produce orthostatic hypotension in ambulatory patients.

Use in Liver Disease

Levorphanol should be administered with caution to patients with extensive liver disease who may be vulnerable to excessive sedation due to increased phamacodynamic sensitivity or impaired metabolism of the drug.

Biliary Surgery

Levorphanol has been shown to cause moderate to marked rises in pressure in the common bile duct when given in analgesic doses. It is not recommended for use in biliary surgery.

Use in Alcoholism or Drug Dependence

Levorphanol has an abuse potential as great as morphine, and the prescription of this drug must always balance the prospective benefits against the risk of abuse and dependence. The use of Levorphanol in patients with a history of alcohol or other drug dependence, either active or in remission, has not been specifically studied (see DRUG ABUSE AND DEPENDENCE).

Precautions

General

As with other opioids, the administration of Levorphanol may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Levorphanol should be administered with caution and the initial dose should be reduced in patients who are elderly or debilitated and in those patients with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, toxic psychosis, prostatic hypertrophy or urethral stricture, acute alcoholism, or delirium tremens.

Information for Patients

If Levorphanol is administered to ambulatory patients, they should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. They should also be warned that concurrent use of Levorphanol with central nervous system depressants (e.g., alcohol, sedatives, hypnotics, other opioids, barbiturates, tricyclic antidepressants, phenothiazines, tranquilizers, skeletal muscle relaxants and antihistamines) may result in additive central nervous system depressant effects. Patients should be made aware of the risk of orthostatic hypotension, dizziness and syncope in ambulatory patients taking Levorphanol.

Drug Interactions

Interactions with Other CNS Agents

Concurrent use of Levorphanol with all central nervous system depressants (e.g., alcohol, sedatives, hypnotics, other opioids, general anesthetics, barbiturates, tricyclic antidepressants, phenothiazines, tranquilizers, skeletal muscle relaxants and antihistamines) may result in additive central nervous system depressant effects. Respiratory depression, hypotension, and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Although no interaction between MAO inhibitors and Levorphanol has been observed, it is not recommended for use with MAO inhibitors.

Most cases of serious or fatal adverse events involving Levorphanol reported to the manufacturer or the FDA have involved either the administration of large initial doses of the drug or too frequent doses of the drug to non-opioid tolerant patients, or the simultaneous administration of Levorphanol with other drugs affecting respiration (see INDIVIDUALIZATION OF DOSAGE and WARNINGS). The initial dose of Levorphanol should be reduced by approximately 50% or more when it is given to patients along with another drug affecting respiration.

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, butorphanol, dezocine and buprenorphine) should NOT be administered to a patient who has received or is receiving a course of therapy with a pure agonist opioid analgesic such as Levorphanol. In opioid-dependent patients, mixed agonist/antagonist analgesics may precipitate withdrawal symptoms.

Use in Ambulatory Patients

Levorphanol has been used in both inpatient and outpatient settings, but both physicians and patients must be aware of the risk of orthostatic hypotension, dizziness and syncope in ambulatory patients.

As with other opioids the use of Levorphanol may impair mental and/or physical abilities required for the performance of potentially hazardous tasks or for the exercise of normal good judgment and patients and staff should be advised accordingly.

Concurrent use of Levorphanol with central nervous system depressants (e.g., alcohol, sedatives, hypnotics, other opioids, barbiturates, tricyclic antidepressants, phenothiazines, tranquilizers, skeletal muscle relaxants and antihistamines) may result in additive central nervous system depressant effects.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No information about the effects of Levorphanol on carcinogenesis, mutagenesis, or fertility is available.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Levorphanol has been shown to be teratogenic in mice when given a single oral dose of 25 mg/kg. The tested dose caused a near 50% mortality of the mouse embryos. There are no adequate and well-controlled studies in pregnant women. Levorphanol should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Babies born to mothers who have been taking opioids regularly prior to delivery may be physically dependent.

A study in rabbits has demonstrated that at doses of 1.5 to 20 mg/kg, Levorphanol administered intravenously crosses the placental barrier and depresses fetal respiration.

Labor and Delivery

The use of Levorphanol in labor and delivery in humans has not been studied. However, as with other opioids, administration of Levorphanol to the mother during labor and delivery may result in respiratory depression in the newborn. Therefore, its use during labor and delivery is not recommended.

Nursing Mothers

Studies of Levorphanol concentrations in breast milk have not been performed. However, morphine, which is structurally similar to Levorphanol, is excreted in human milk. Because of the potential for serious adverse reactions from Levorphanol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Levorphanol is not recommended in children under the age of 18 years as the safety and efficacy of the drug in this population has not been established.

Geriatric Use

The initial dose of the drug should be reduced by 50% or more in the infirm elderly patient, even though there have been no reports of unexpected adverse events in older populations. All drugs of this class may be associated with a profound or prolonged effect in elderly patients for both pharmacokinetic and pharmacodynamic reasons and caution is indicated.

Adverse Reactions

In approximately 1400 patients treated with Levorphanol in controlled clinical trials, the type and incidence of side effects were those expected of an opioid analgesic, and no unforeseen or unusual toxicity was reported.

Drugs of this type are expected to produce a cluster of typical opioid effects in addition to analgesia, consisting of nausea, vomiting, altered mood and mentation, pruritus, flushing, difficulties in urination, constipation, and biliary spasm. The frequency and intensity of these effects appears to be dose related. Although listed as adverse events these are expected pharmacologic actions of these drugs and should be interpreted as such by the clinician.

The following adverse events have been reported with the use of Levorphanol:

Body as a Whole: abdominal pain, dry mouth, sweating

Cardiovascular System: cardiac arrest, shock, hypotension, arrhythmias including bradycardia and tachycardia, palpitations, extra-systoles

Digestive System: nausea, vomiting, dyspepsia, biliary tract spasm

Nervous System: coma, suicide attempt, convulsions, depression, dizziness, confusion, lethargy, abnormal dreams, abnormal thinking, nervousness, drug withdrawal, hypokinesia, dyskinesia, hyperkinesia, CNS stimulation, personality disorder, amnesia, insomnia

Respiratory System: apnea, cyanosis, hypoventilation

Skin & Appendages: pruritus, urticaria, rash, injection site reaction

Special Senses: abnormal vision, pupillary disorder, diplopia

Urogenital System: kidney failure, urinary retention, difficulty urinating

Drug Abuse and Dependence

WARNING: May Be Habit Forming.

Levorphanol is a schedule II Controlled Substance. All drugs of this class (mu-opioids of the morphine type) are habit forming and should be stored, prescribed, used, and disposed of accordingly. Psychological/physical dependence and tolerance may develop upon repeated administration of Levorphanol.

Discontinuation of Levorphanol after chronic use has been reported to result in withdrawal syndromes, and some reports of overuse and self-reported addiction have been received. Neither withdrawal nor withdrawal symptoms are usually expected in postoperative patients who used the drug for less than a week or in patients who are gradually tapered off the drug after longer use.

Overdosage

Most reports of overdosage known to the manufacturer and to the FDA involve three clinical situations. These are: 1) the use of larger than recommended doses or too frequent doses, 2) administration of the drug to children or small adults without any reduction in dosage, and 3) the use of the drug in ordinary dosage in patients compromised by concurrent illness.

As with all opioids, overdose can occur due to accidental or intentional misuse of this product, especially in infants and children who may gain access to the drug in the home. Based on its pharmacology, Levorphanol overdosage would be expected to produce signs of respiratory depression, cardiovascular failure (especially in predisposed patients), and/or central nervous system depression. Serious overdosage with Levorphanol is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, periodic breathing, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Treatment

The specific treatment of suspected Levorphanol tartrate overdosage is immediate establishment of an adequate airway and ventilation, followed (if necessary) by intravenous naloxone. The respiratory and cardiac status of the patient should be continuously monitored and appropriate supportive measures instituted, such as oxygen, intravenous fluids, and/or vasopressors if required. Physicians are reminded that the duration of Levorphanol action far exceeds the duration of action of naloxone, and repeated dosing with naloxone may be required. Naloxone should be administered cautiously to persons known or suspected to be physically dependent on Levorphanol. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute abstinence syndrome. If necessary to administer naloxone to the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Levorphanol Dosage and Administration

Oral

The usual recommended starting dose for oral administration is 2 mg. This may be repeated in 6 to 8 hours as needed, provided the patient is assessed for signs of hypoventilation and excessive sedation. If necessary, the dose may be increased to up to 3 mg every 6 to 8 hours, after adequate evaluation of the patient’s response. Higher doses may be appropriate in opioid tolerant patients. Dosage should be adjusted according to the severity of the pain; age, weight and physical status of the patient; the patient’s underlying diseases; use of concomitant medications; and other factors (see INDIVIDUALIZATION OF DOSAGE, WARNINGS and PRECAUTIONS). Total oral daily doses of more than 6 to 12 mg in 24 hours are generally not recommended as starting doses in nonopioid tolerant patients; lower total daily doses may be appropriate.

Use in Chronic Pain

The dosage of Levorphanol in patients with cancer or with other conditions for which chronic opioid therapy is indicated must be individualized (see INDIVIDUALIZATION OF DOSAGE). Levorphanol is 4 to 8 times as potent as morphine and has a longer half-life. Because there is incomplete, cross-tolerance among opioids, when converting a patient from morphine to Levorphanol, the total daily dose of Levorphanol should begin at approximately 1/15 to 1/12 of the total daily dose of oral morphine that such patients had previously required and then the dose should be adjusted to the patient’s clinical response. If a patient is to be placed on fixed-schedule dosing (round-the-clock) with this drug, care should be taken to allow adequate time after each dose change (approximately 72 hours) for the patient to reach a new steady-state before a subsequent dose adjustment to avoid excessive sedation due to drug accumulation.

Note: As with all controlled substances, abuse by health care personnel is possible and the drug should be handled accordingly.

How is Levorphanol Supplied

Levorphanol Tartrate Tablets USP, 2 mg

White, scored tablets (Identified 54 410).

NDC 0054-0438-25: Bottles of 100 tablets.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP/NF.

DEA Order Form Required

10003340/04 Revised July 2011

©RLI, 2011

PRINCIPAL DISPLAY PANEL

NDC 0054-0438-25: Bottles of 100 tablets

Roxane Laboratories Inc.

Levorphanol TARTRATE  Levorphanol tartrate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0054-0438 Route of Administration ORAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Levorphanol TARTRATE (Levorphanol) Levorphanol TARTRATE 2 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE   STARCH, CORN   MAGNESIUM STEARATE

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 6mm Flavor Imprint Code 54;410 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0054-0438-25 100 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA074278	03/31/2000

Labeler - Roxane Laboratories, Inc (833490464)

Registrant - Roxane Laboratories, Inc (833490464)

Establishment
Name	Address	ID/FEI	Operations
Boehringer Ingelheim Roxane Inc		058839929	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Mallinckrodt Inc. (Covidien)		163205300	API MANUFACTURE

Revised: 07/2011Roxane Laboratories, Inc

More Levorphanol resources

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

• Levorphanol MedFacts Consumer Leaflet (Wolters Kluwer)


• levorphanol Concise Consumer Information (Cerner Multum)


• levorphanol Advanced Consumer (Micromedex) - Includes Dosage Information


• Levo-Dromoran Monograph (AHFS DI)

Compare Levorphanol with other medications

• Light Sedation
• Pain

PediaCare Long-Acting Cough/Cold Chewable Tablets

Pronunciation: sue-do-eh-FED-rin/dex-troe-meth-OR-fan
Generic Name: Pseudoephedrine/Dextromethorphan
Brand Name: PediaCare Long-Acting Cough/Cold

PediaCare Long-Acting Cough/Cold Chewable Tablets are used for:

Relieving congestion and cough due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

PediaCare Long-Acting Cough/Cold Chewable Tablets are a decongestant and cough suppressant combination. It works by constricting blood vessels and reducing swelling in the nasal passages, which helps you to breathe more easily. The cough suppressant works in the brain to help decrease the cough reflex.

Do NOT use PediaCare Long-Acting Cough/Cold Chewable Tablets if:

• you are allergic to any ingredient in PediaCare Long-Acting Cough/Cold Chewable Tablets


• you have severe high blood pressure, rapid heartbeat, or other severe heart problems (eg, heart blood vessel disease)


• you have taken furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using PediaCare Long-Acting Cough/Cold Chewable Tablets:

Some medical conditions may interact with PediaCare Long-Acting Cough/Cold Chewable Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, plan to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of glaucoma, an enlarged prostate gland or other prostate problems, heart problems, diabetes, high blood pressure, blood vessel problems, adrenal gland problems, an overactive thyroid, seizures, or stroke


• if you have chronic cough, chronic obstructive pulmonary disease (COPD), or other lung problems (eg, asthma, chronic bronchitis, emphysema), or if your cough produces large amounts of mucus

Some MEDICINES MAY INTERACT with PediaCare Long-Acting Cough/Cold Chewable Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), COMT inhibitors (eg, tolcapone), furazolidone, indomethacin, MAO inhibitors (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because the risk of side effects from PediaCare Long-Acting Cough/Cold Chewable Tablets may be increased


• Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased


• Bromocriptine because the risk of side effects may be increased by PediaCare Long-Acting Cough/Cold Chewable Tablets


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by PediaCare Long-Acting Cough/Cold Chewable Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if PediaCare Long-Acting Cough/Cold Chewable Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use PediaCare Long-Acting Cough/Cold Chewable Tablets:

Use PediaCare Long-Acting Cough/Cold Chewable Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• PediaCare Long-Acting Cough/Cold Chewable Tablets may be taken with or without food.


• Chew thoroughly before swallowing.


• If you miss a dose of PediaCare Long-Acting Cough/Cold Chewable Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use PediaCare Long-Acting Cough/Cold Chewable Tablets.

Important safety information:

• PediaCare Long-Acting Cough/Cold Chewable Tablets may cause dizziness or drowsiness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to PediaCare Long-Acting Cough/Cold Chewable Tablets. Using PediaCare Long-Acting Cough/Cold Chewable Tablets alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Do not take appetite suppressants while you are taking PediaCare Long-Acting Cough/Cold Chewable Tablets without checking with your doctor.


• PediaCare Long-Acting Cough/Cold Chewable Tablets contains pseudoephedrine. Before you begin taking any new prescription or nonprescription medicine, read the ingredients to see if it also contains pseudoephedrine. If it does or if you are uncertain, contact your doctor or pharmacist.


• Do NOT exceed the recommended dose or take PediaCare Long-Acting Cough/Cold Chewable Tablets for longer than prescribed without checking with your doctor.


• If your symptoms do not improve within 5 to 7 days or if they become worse, check with your doctor.


• PediaCare Long-Acting Cough/Cold Chewable Tablets may interfere with certain lab test results. Make sure that all of your doctors and lab personnel know that you are taking PediaCare Long-Acting Cough/Cold Chewable Tablets.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using PediaCare Long-Acting Cough/Cold Chewable Tablets.


• Use PediaCare Long-Acting Cough/Cold Chewable Tablets with caution in the ELDERLY because they may be more sensitive to its effects.


• Caution is advised when using PediaCare Long-Acting Cough/Cold Chewable Tablets in CHILDREN because they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking PediaCare Long-Acting Cough/Cold Chewable Tablets, discuss with your doctor the benefits and risks of using PediaCare Long-Acting Cough/Cold Chewable Tablets during pregnancy. It is unknown if PediaCare Long-Acting Cough/Cold Chewable Tablets are excreted in breast milk. Do not breast-feed while taking PediaCare Long-Acting Cough/Cold Chewable Tablets.

Possible side effects of PediaCare Long-Acting Cough/Cold Chewable Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Dizziness; excitability; headache; nausea; nervousness or anxiety; trouble sleeping; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; tremor.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of PediaCare Long-Acting Cough/Cold Chewable Tablets:

Store PediaCare Long-Acting Cough/Cold Chewable Tablets at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep PediaCare Long-Acting Cough/Cold Chewable Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about PediaCare Long-Acting Cough/Cold Chewable Tablets, please talk with your doctor, pharmacist, or other health care provider.


• PediaCare Long-Acting Cough/Cold Chewable Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about PediaCare Long-Acting Cough/Cold Chewable Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More PediaCare Long-Acting Cough/Cold resources

• PediaCare Long-Acting Cough/Cold Use in Pregnancy & Breastfeeding
• PediaCare Long-Acting Cough/Cold Drug Interactions
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