Oseltamivir: Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Oseltamivir: Patient drug information" and see "Oseltamivir: Pediatric drug information" )

For abbreviations and symbols that may be used in Lexicomp (show table ) Special Alerts Expanded Pediatric Use for Oseltamivir (Tamiflu®) December 2012

The Food and Drug Administration (FDA) has expanded the use of oseltamivir (Tamiflu®) for the treatment of influenza in children as young as 2 weeks old who have shown symptoms of influenza for ≤2 days. Previously, Tamiflu® was only FDA approved for influenza treatment in children ≥1 year of age.

Recommended dosing for influenza treatment in children <1 year is 3 mg/kg twice daily for 5 days which requires that each dose be calculated using the child’s exact weight. In addition, these smaller doses will require that the pharmacist provide a proper dosing device so that parents can accurately measure and administer the correct dose. The dosing device that is currently packaged with Tamiflu® powder for oral suspension will not accurately measure the dose and should not be used for children <1 year of age.

For more information, see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333205.htm?source =govdelivery

Brand Names: U.S.

 Tamiflu

Brand Names: Canada

 Tamiflu®

Pharmacologic Category

 Antiviral Agent;

 Neuraminidase Inhibitor

Dosing: Adult

Influenza prophylaxis: Oral: 75 mg once daily; initiate prophylaxis within 48 hours of contact with an infected individual; duration of prophylaxis: 10 days (manufacturer recommendation) or alternatively 7 days (CDC, 2012). During community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised.

Prophylaxis (institutional outbreak; CDC, 2012): Continue for ≥2 weeks and until ~7 days after identification of illness onset in the last patient

Influenza treatment: Oral: 75 mg twice daily initiated within 48 hours of onset of symptoms; duration of treatment: 5 days

Note: Hospitalized patients with severe influenza infection may require longer (eg, ≥10 days) treatment courses. Some experts also recommend empirically doubling the treatment dose. Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza regardless of the time of presentation from symptom onset (CDC, 2011); may be administered via naso- or orogastric tube in mechanically-ventilated patients (Taylor, 2008).

Dosing: Pediatric

(For additional information see "Oseltamivir: Pediatric drug information" )

Influenza prophylaxis: Oral: Initiate prophylaxis within 48 hours of contact with an infected individual

Manufacturer’s recommendation:

Children: 1-12 years:

≤15 kg: 30 mg once daily

>15 kg to ≤23 kg: 45 mg once daily

>23 kg to ≤40 kg: 60 mg once daily

>40 kg: 75 mg once daily

Adolescents ≥13 years: Refer to adult dosing.

Alternate recommendations:

Children 3-11 months (unlabeled dosing; AAP, 2010): Note: Dosing based on age (use only if weight not available)

3-5 months: 20 mg once daily

6-11 months: 25 mg once daily

Children <12 months (unlabeled dosing, CDC, 2012): Note: Prophylaxis is not recommended for infants <3 months of age unless clinically critical; weight- based dosing recommendations are not intended for premature neonates: 3 mg/kg/dose once daily

Children 3-23 months (unlabeled dosing, IDSA/PIDS, 2011):

3-8 months: 3 mg/kg/dose once daily (do not exceed maximum dose of weight- based dosing)

9-23 months: 3.5 mg/kg/dose once daily (do not exceed maximum dose of weight-based dosing)

Prophylaxis duration: Individual/household exposure:

Manufacturer recommendation: 10 days

Alternate recommendations: 7 days (CDC, 2012)

Community/institutional outbreak:

Manufacturer recommendation: May be used for up to 6 weeks

Alternate recommendations: Continue for ≥2 weeks and until ~7 days after identification of illness onset in the last patient (CDC, 2012) or until influenza activity in community subsides or immunity obtained from immunization (IDSA/PIDS, 2011). During community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised.

Influenza treatment: Oral: Initiate treatment within 48 hours of onset of symptoms; duration of treatment: 5 days unless severely ill and hospitalized. Note: Hospitalized patients may require longer (eg, ≥10 days) treatment courses. Some experts also recommend empirically doubling the treatment dose. Doubling the dose in adult outpatients was not associated with increased adverse events. As no double-dose studies have been published in children, use caution. Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza regardless of the time of presentation from symptom onset (CDC, 2011); may be administered via naso- or orogastric tube in mechanically- ventilated patients (Taylor, 2008).

Manufacturer’s recommendation: Note: The following dosing is also supported by some clinicians (IDSA/PIDS, 2011):

Infants ≥2 weeks: 3 mg/kg/dose twice daily

Children: 1-12 years:

≤15 kg: 30 mg twice daily

>15 kg to ≤23 kg: 45 mg twice daily

>23 kg to ≤40 kg: 60 mg twice daily

>40 kg: 75 mg twice daily

Adolescents ≥13 years: Refer to adult dosing.

Alternate recommendations:

Infants <2 weeks (unlabeled dosing, CDC, 2012): Note: Weight-based dosing recommendations are not intended for premature neonates: 3 mg/kg/dose twice daily.

Infants <12 months (unlabeled dosing; AAP, 2010): Note: Dosing based on age (use only if weight not available):

<3 months: 12 mg twice daily

3-5 months: 20 mg twice daily

6-11 months: 25 mg twice daily Infants and Children <24 months (unlabeled dosing; IDSA/PIDS, 2011): Note: Do not exceed maximum dose of weight-based dosing.

Infants, premature: 1 mg/kg/dose twice daily

0-8 months: 3 mg/kg/dose twice daily

9-23 months: 3.5 mg/kg/dose twice daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Treatment: Adults:

U.S. labeling: Clcr 10-30 mL/minute: 75 mg once daily for 5 days

Canadian labeling:

Clcr >30-60 mL/minute: 30 mg twice daily for 5 days

Clcr 10-30 mL/minute: 30 mg once daily for 5 days

High-dose treatment (unlabeled [eg, severely-ill hospitalized patients with 2009 H1N1 influenza]): Currently no data are available; consider 150 mg once daily

Prophylaxis: Adults:

U.S. labeling: Clcr 10-30 mL/minute: 75 mg every other day or 30 mg once daily

Canadian labeling:

Clcr >30-60 mL/minute: 30 mg once daily for 10-14 days

Clcr 10-30 mL/minute: 30 mg every other day for 10-14 days

CAPD: Adults:

Unlabeled dose: 30 mg once weekly (Robson, 2006)

Canadian labeling (not in U.S. labeling):

Treatment: 30 mg prior to start of dialysis

Prophylaxis: 30 mg prior to start of dialysis, then 30 mg every 7 days for 10-14 days

Hemodialysis:

Children >1 year (unlabeled dose; Schreuder, 2010):

≤15 kg: 7.5 mg after each hemodialysis session

>15 kg to ≤23 kg: 10 mg after each hemodialysis session

>23 kg to ≤40 kg: 15 mg after each hemodialysis session

>40 kg: 30 mg after each hemodialysis session

Adults:

Unlabeled dose: 30 mg after every other session (Robson, 2006)

Canadian labeling (not in U.S. labeling): Treatment: 30 mg prior to dialysis; if symptomatic between dialysis sessions, then administer 30 mg after each dialysis session over period of 5 days

Prophylaxis: 30 mg prior to dialysis, then 30 mg after every other dialysis session for period of 10-14 days

Dosing: Hepatic Impairment

Mild-to-moderate impairment: No adjustment necessary

Severe impairment: Pharmacokinetics and safety have not been evaluated

Dosage Forms: U.S.

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

Capsule, Oral, as phosphate:

Tamiflu: 30 mg, 45 mg, 75 mg

Suspension Reconstituted, Oral, as base:

Tamiflu: 6 mg/mL (60 mL) [contains saccharin sodium, sodium benzoate; tutti-frutti flavor]

Generic Equivalent Available: U.S.

No

Administration

May be administered without regard to meals; take with food to improve tolerance.

Capsules may be opened and mixed with sweetened liquid (eg, chocolate syrup). Administer oral suspension using the supplied oral syringe (exception: for children <1 year, a smaller volume [ie, <10 mL] oral syringe should be used in place of the supplied oral syringe to ensure accurate dosing); shake well.

Mechanically-ventilated critically-ill patients: May administer via naso- or orogastric (NG/OG) tube. For a 150 mg dose, dissolve powder from two 75 mg capsules in 20 mL of sterile water and inject down the NG/OG tube; follow with a 10 mL sterile water flush (Taylor, 2008).

Use

Treatment of uncomplicated acute illness due to influenza (A or B) infection in children ≥2 weeks and adults who have been symptomatic for no more than 2 days; prophylaxis against influenza (A or B) infection in children ≥1 year of age and adults

The Advisory Committee on Immunization Practices (ACIP) recommends that treatment be considered for the following:

• Persons with severe, complicated or progressive illness

• Hospitalized persons

• Persons at higher risk for influenza complications:

- Children <2 years of age (highest risk in children <6 months of age) - Adults ≥65 years of age

- Persons with chronic disorders of the pulmonary (including asthma) or cardiovascular systems (except hypertension)

- Persons with chronic metabolic diseases (including diabetes mellitus), hepatic disease, renal dysfunction, hematologic disorders (including sickle cell disease), or immunosuppression (including immunosuppression caused by medications or HIV)

- Persons with neurologic/neuromuscular conditions (including conditions such as spinal cord injuries, seizure disorders, cerebral palsy, stroke, mental retardation, moderate to severe developmental delay, or muscular dystrophy) which may compromise respiratory function, the handling of respiratory secretions, or that can increase the risk of aspiration

- Pregnant or postpartum women (≤2 weeks after delivery)

- Persons <19 years of age on long-term aspirin therapy

- American Indians and Alaskan Natives

- Persons who are morbidly obese (BMI ≥40)

- Residents of nursing homes or other chronic care facilities

• Use may also be considered for previously healthy, nonhigh-risk outpatients with confirmed or suspected influenza based on clinical judgment when treatment can be started within 48 hours of illness onset.

The ACIP recommends that prophylaxis be considered for the following:

• Postexposure prophylaxis may be considered for family or close contacts of suspected or confirmed cases, who are at higher risk of influenza complications, and who have not been vaccinated against the circulating strain at the time of the exposure.

• Postexposure prophylaxis may be considered for unvaccinated healthcare workers who had occupational exposure without protective equipment.

• Pre-exposure prophylaxis should only be used for persons at very high risk of influenza complications who cannot be otherwise protected at times of high risk for exposure.

• Prophylaxis should also be administered to all eligible residents of institutions that house patients at high risk when needed to control outbreaks.

The ACIP recommends that treatment and prophylaxis be given to children <1 year of age when indicated.

Medication Safety Issues Sound-alike/look-alike issues:

Tamiflu® may be confused with Tambocor™, Thera-Flu® Other safety concerns:

Oseltamivir (Tamiflu®) oral suspension is available in a 6 mg/mL concentration and is packaged with an oral syringe calibrated in milliliters up to a total of 10 mL. Instructions to the patient should be provided based on these units of measure (ie, mL). When providing oseltamivir suspension for children <1 year of age, use a lower calibrated (ie, <10 mL) oral syringe to ensure accurate dosing.

When commercially-prepared oseltamivir oral suspension is not available, an extemporaneously prepared suspension may be compounded to provide a 6 mg/mL concentration.

Adverse Reactions Significant

>10%: Gastrointestinal: Vomiting (2% to 15%)

1% to 10%:

Gastrointestinal: Nausea (4% to 10%), abdominal pain (2% to 5%), diarrhea (1% to 3%)

Ocular: Conjunctivitis (1%)

Respiratory: Epistaxis (1%)

<1% (Limited to important or life-threatening): Allergy, anaphylactic/anaphylactoid reaction, angina, arrhythmia, confusion, erythema multiforme, fracture, gastrointestinal bleeding, hemorrhagic colitis, hepatitis, liver function tests abnormal, neuropsychiatric events, pseudomembranous colitis, pyrexia, seizure, Stevens-Johnson syndrome, swelling of face or tongue, toxic epidermal necrolysis

Contraindications

Hypersensitivity to oseltamivir or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity: Rare but severe hypersensitivity reactions (anaphylaxis, severe dermatologic reactions) have been associated with use.

• Neuropsychiatric events: Rare occurrences of neuropsychiatric events (including confusion, delirium, hallucinations, and/or self-injury) have been reported primarily in pediatric patients from postmarketing surveillance; direct causation is difficult to establish (influenza infection may also be associated with behavioral and neurologic changes). Monitor closely for signs of any unusual behavior.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with chronic cardiac disease; efficacy has not been established.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment; safety and efficacy have not been established.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required for creatinine clearance <30 mL/minute.

• Respiratory disease: Use with caution in patients with respiratory disease; efficacy has not been established.

Special populations: • Immunocompromised patients: Use with caution in immunocompromised patients; safety and efficacy for treatment or prophylaxis in immunocompromised patients have not been established.

Other warnings/precautions:

• Appropriate use: Oseltamivir is not a substitute for the influenza virus vaccine. It has not been shown to prevent primary or concomitant bacterial infections that may occur with influenza virus. Antiviral treatment should begin within 48 hours of symptom onset. However, the CDC recommends that treatment may still be beneficial and should be started in hospitalized patients with severe, complicated or progressive illness if >48 hours. Treatment should not be delayed while awaiting results of laboratory tests for influenza. Nonhospitalized persons who are not at high risk for developing severe or complicated illness and who have a mild disease are not likely to benefit if treatment is started >48 hours after symptom onset. Nonhospitalized persons who are already beginning to recover do not need treatment.

Metabolism/Transport Effects

None known.

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid anti- influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Risk D: Consider therapy modification

Probenecid: May increase serum concentrations of the active metabolite(s) of Oseltamivir. Management: Consider a change in therapy when using oseltamivir together with probenecid; reduced oseltamivir dose may be necessary. Increase monitoring for adverse events, such as thrombocytopenia. Risk D: Consider therapy modification

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

In animal reproduction studies, a dose-dependent increase in the rates of minor skeleton abnormalities was found in exposed offspring. The rate of each abnormality remained within the background rate of occurrence in the species studied. Oseltamivir phosphate and its active metabolite oseltamivir carboxylate cross the placenta (in vitro data). An increased risk of adverse neonatal outcomes has generally not been observed following maternal use of oseltamivir during pregnancy. Untreated influenza infection is associated with an increased risk of adverse events to the fetus and an increased risk of complications or death to the mother. Oseltamivir and zanamivir are currently recommended for the treatment or prophylaxis of influenza in pregnant women and women up to 2 weeks postpartum. Oseltamivir and zanamivir are currently recommended as an adjunct to vaccination and should not be used as a substitute for vaccination in pregnant women (consult current CDC guidelines). Lactation

Enters breast milk/not recommended

Breast-Feeding Considerations

Small amounts of oseltamivir and oseltamivir carboxylate have been detected in breast milk. Breast-feeding is not recommended by the manufacturer. According to the CDC, breast-feeding while taking oseltamivir can be continued. The CDC recommends that women infected with the influenza virus follow general precautions (eg, frequent hand washing) to decrease viral transmission to the child. Mothers with influenza-like illnesses at delivery should consider avoiding close contact with the infant until they have received 48 hours of antiviral medication, fever has resolved, and cough and secretions can be controlled. These measures may help decrease (but not eliminate) the risk of transmitting influenza to the newborn. During this time, breast milk can be expressed and bottle-fed to the infant by another person who is well. Protective measures, such as wearing a face mask, changing into a clean gown or clothing, and strict hand hygiene should be continued by the mother for ≥7 days after the onset of symptoms or until symptom-free for 24 hours. Infant care should be performed by a noninfected person when possible (consult current CDC guidelines). Influenza may cause serious illness in postpartum women and prompt evaluation for febrile respiratory illnesses is recommended.

Dietary Considerations

Take without regard to meals; take with food to improve tolerance.

Pricing: U.S. (Medi-Span®)

Capsules (Tamiflu Oral)

30 mg (10): $111.74

45 mg (10): $111.74

75 mg (10): $121.80

Suspension (reconstituted) (Tamiflu Oral)

6 mg/mL (60 mL): $121.80

Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

Monitoring Parameters

Signs or symptoms of unusual behavior, including attempts at self-injury, confusion, and/or delirium

Critically-ill patients: Repeat rRT-PCR or viral culture may help to determine on-going viral replication

International Brand Names

 Ao Er Fei (CL);

 GPO-A-Flu (TH);

 Omiflu (MY);

 Tamiflu (AR, AT, AU, BE, BG, BR, CH, CL, CN, CO, CZ, DE, DK, EC, EE, ES, FI, FR, GB, GR, HK, HN, HU, IE, IL, IT, JP, KP, MT, MX, NL, NO, NZ, PE, PH, PK, PL, PT, PY, RU, SE, SG, SK, TH, TR, TW, UY)

Mechanism of Action

Oseltamivir, a prodrug, is hydrolyzed to the active form, oseltamivir carboxylate (OC). OC inhibits influenza virus neuraminidase, an enzyme known to cleave the budding viral progeny from its cellular envelope attachment point (neuraminic acid) just prior to release.

Pharmacodynamics/Kinetics

Absorption: Well absorbed

Distribution: Vd: 23-26 L (oseltamivir carboxylate)

Protein binding, plasma: Oseltamivir carboxylate: 3%; Oseltamivir: 42%

Metabolism: Hepatic (90%) to oseltamivir carboxylate; neither the parent drug nor active metabolite has any effect on the cytochrome P450 system

Bioavailability: 75% as oseltamivir carboxylate

Half-life elimination: Oseltamivir: 1-3 hours; Oseltamivir carboxylate: 6-10 hours

Excretion: Urine (>90% as oseltamivir carboxylate); feces Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. American Academy of Pediatrics, Committee on Infectious Diseases, “Policy, Statement -- Recommendations for Prevention and Control of influenza in Children, 2010-2011,” Pediatrics, 2010, 126(4):816-26. [PubMed 20805143] 2. Aoki FY, Allen UD, Stiver HG, et al, AMMI Canada Guidelines, "The Use of Antiviral Drugs for Influenza: Guidance for Practitioners 2012/2013,” Can J Infect Dis Med Microbiol, 2012, 23(4):e79-92. Available at http://www.ammi.ca/media/48038/14791_aoki_final.pdf.pdf. 3. Bradley JS, Byington CL, Shah SS, et al. “The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America”, Clin Infect Dis, 2011, 53(7):e25-76. [PubMed21880587] 4. Centers for Disease Control and Prevention (CDC), “Intensive-Care Patients With Severe Novel Influenza A (H1N1) Virus Infection - Michigan, June 2009,” MMWR Morb Mortal Wkly Rep, 2009, 58(27):749-52. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5827a4.htm [PubMed 19609249] 5. Centers for Disease Control and Prevention (CDC), “Influenza Antiviral Medications: Summary for Clinicians.” Available at http://www.cdc.gov/flu/professionals/antivirals/summary- clinicians.htm. Accessed on November 26, 2012. 6. Centers for Disease Control and Prevention (CDC), "Influenza Division, National Center for Immunization and Respiratory Diseases. Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza --- Recommendations of the Advisory Committee on Immunization Practices (ACIP)," MMWR Surveill Summ, 2011, 60(1):1-28. [PubMed 21248682] 7. Harper SA, Bradley JS, Englund JA, et al, “Seasonal Influenza in Adults and Children-- Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management: Clinical Practice Guidelines of the Infectious Diseases Society of America,” Clin Infect Dis, 2009, 48(8):1003-32. [PubMed 19281331] 8. He G, Massarella J, and Ward P, “Clinical Pharmacokinetics of the Prodrug Oseltamivir and Its Active Metabolite Ro 64-0802,” Clin Pharmacokinet, 1999, 37(6):471-84. [PubMed 10628898] 9. Jain S, Kamimoto L, Bramley AM, et al, “Hospitalized Patients With 2009 H1N1 Influenza in the United States, April-June 2009,” N Engl J Med, 2009, 361(20):1935-44. [PubMed 19815859] 10. Okumura A, Kubota T, and Kato T, “Oseltamivir and Delirious Behavior in Children With Influenza,” Pediatr Infect Dis J, 2006, 25(6):572. 11. Robson R, Buttimore A, Lynn K, et al, “The Pharmacokinetics and Tolerability of Oseltamivir Suspension in Patients on Haemodialysis and Continuous Ambulatory Peritoneal Dialysis,” Nephrol Dial Transplant, 2006, 21(9):2556-62. [PubMed 16799169] 12. Schreuder MF, van der Flier M, Knops NB, et al, “Oseltamivir Dosing in Children Undergoing Hemodialysis,” Clin Infect Dis, 2010, 50(10):1427-8. [PubMed 20397934] 13. Taylor WRJ, Thinh BN, Anh GT, et al, “Oseltamivir is Adequately Absorbed Following Nasogastric Administration to Adult Patients With Severe H5N1 Influenza,” PLoS One, 2008, 3(10):e3410. [PubMed18923671] 14. Wentges-van Holthe N, van Eijkeren M, and van der Laan JW, “Oseltamivir and Breastfeeding,” Int J Infect Dis, 2008, 12(4):451. [PubMed 18243025]

Topic 9460 Version 45.0

Ribavirin: Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Ribavirin: Patient drug information" and see "Ribavirin: Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table) ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Brand Names: U.S.

 Copegus®;

 Rebetol®;

 Ribasphere®;

 Ribasphere® RibaPak®;

 Virazole® Brand Names: Canada

 Virazole®

Pharmacologic Category

 Antiviral Agent

Dosing: Adult

Note: Oral solution may be used those unable to swallow capsules.

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2b): Oral capsule, oral solution (Rebetol®, Ribasphere®): Note: Recommended therapy duration [manufacturer labeling]: Genotype 1: 48 weeks; genotypes 2,3: 24 weeks); recommended therapy duration for patients who previously failed therapy: 48 weeks [regardless of genotype])

≤65 kg: 800 mg daily (400 mg in the morning and evening)

66-80 kg: 1000 mg daily (400 mg in the morning, 600 mg in the evening)

81-105 kg: 1200 mg daily (600 mg in the morning, 600 mg in the evening)

>105 kg: 1400 mg daily (600 mg in the morning, 800 mg in the evening)

Chronic hepatitis C monoinfection (in combination with interferon alfa-2b): Oral capsule (Rebetol®, Ribasphere®): Note: Individualized therapy duration [manufacturer labeling] 24-48 weeks):

≤75 kg: 1000 mg daily (400 mg in the morning, 600 mg in the evening)

>75 kg: 1200 mg daily (600 mg in the morning, 600 mg in the evening)

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2a): Oral tablet (Copegus®, Ribasphere®):

Genotype 1,4:

<75 kg: 1000 mg daily in 2 divided doses for 48 weeks

≥75 kg: 1200 mg daily in 2 divided doses for 48 weeks

Genotype 2,3: 800 mg daily in 2 divided doses for 24 weeks

Chronic hepatitis C coinfection with HIV (in combination with peginterferon alfa-2a): Oral tablet (Copegus®, Ribasphere®): 800 mg daily in 2 divided doses for 48 weeks (regardless of genotype)

Alternative recommendation: American Association for the Study of Liver Diseases (AASLD) guidelines:Adults with chronic hepatitis C infection (Ghany, 2009): Treatment of choice: Ribavirin plus peginterferon; clinical condition and ability of patient to tolerate therapy should be evaluated to determine length and/or likely benefit of therapy. Recommended treatment duration (AASLD guidelines): Genotypes 1,4: 48 weeks; Genotypes 2,3: 24 weeks; Coinfection with HIV: 48 weeks. RSV infection in hematopoietic cell or heart/lung transplant recipients (unlabeled use): Aerosol inhalation: 2000 mg (over 2 hours) every 8 hours (Boeckh, 2007; Liu, 2010)

Note: Heart/lung transplant recipients also received IVIG, methylprednisolone and palivizumab. Dosage and protocol may be institution specific. (Boeckh, 2007; Chemaly, 2006; Liu, 2010).

Dosing: Pediatric

(For additional information see "Ribavirin: Pediatric drug information")

Chronic hepatitis C monoinfection (in combination with pegylated or nonpegylated interferon alfa-2b):

Children ≥3 years: Oral capsule or solution (Rebetol®, Ribasphere®): Note: Oral solution should be used in children <47 kg, or those unable to swallow capsules. Children who start treatment prior to age 18 years should continue on pediatric dosing regimen through therapy completion. Recommended therapy duration (manufacturer labeling): Genotypes 2,3: 24 weeks; all other genotypes: 48 weeks

Oral capsule, oral solution dosing recommendations:

<47 kg: 15 mg/kg/day in 2 divided doses (morning and evening) as oral solution

47-59 kg: 800 mg daily (400 mg in morning and evening)

60-73 kg: 1000 mg daily (400 mg in morning and 600 mg in the evening)

>73 kg: 1200 mg daily (600 mg in morning and evening)

Alternative recommendations: American Association for the Study of Liver Diseases (AASLD) guidelines: Children 2-17 years with chronic hepatitis C infection (Ghany, 2009): Treatment of choice: Ribavirin 15 mg/kg daily (in combination with SubQ peginterferon alfa-2b) once weekly for 48 weeks

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2a):

Children ≥5 years: Oral tablet (Copegus®): Note: Assess child’s ability to swallow tablet; children who start treatment prior to age 18 years should continue on pediatric dosing regimen through therapy completion. Recommended therapy duration (manufacturer labeling): Genotypes 2,3: 24 weeks; all other genotypes: 48 weeks

23-33 kg: 400 mg daily (200 mg in the morning and evening)

34-46 kg: 600 mg daily (200 mg in the morning and 400 mg in the evening)

47-59 kg: 800 mg daily (400 mg in the morning and evening)

60-74 kg: 1000 mg daily (400 mg in the morning and 600 mg in the evening)

≥75 kg: 1200 mg daily (600 mg in the morning and evening)

RSV infection: Infants and Children: Aerosol inhalation: Use with Viratek® small particle aerosol generator (SPAG-2): A concentration of 20 mg/mL (6 g reconstituted with 300 mL of sterile water without preservatives) administered for 12-18 hours/day for 3 days, up to 7 days in length.

Dosing: Geriatric

Refer to adult dosing. Dosing: Renal Impairment

CHC infection: Oral:

Rebetol® capsules/solution, Ribasphere® capsules: Adults:

Clcr ≥50 mL/minute: No dosage adjustments are recommended.

Clcr <50 mL/minute: Use is contraindicated.

Ribasphere® tablets: Adults:

Clcr ≥50 mL/minute: No dosage adjustments are recommended.

Clcr <50 mL/minute: Use is not recommended.

Copegus® tablets: Adults:

Clcr >50 mL/minute: No dosage adjustments are recommended.

Clcr 30-50 mL/minute: Alternate 200 mg and 400 mg every other day.

Clcr <30 mL/minute: 200 mg once daily.

ESRD requiring hemodialysis: 200 mg once daily.

Note: The dose of Copegus® should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop it should be discontinued, if appropriate, until the adverse reactions resolve or decrease in severity. If abnormalitis persist after restarting, therapy should be discontinued.

Dosing: Hepatic Impairment

CHC infection: Hepatic decompensation (Child-Pugh class B and C): Manufacturer’s labeling: Oral tablets: Use contraindicated.

Dosing: Adjustment for Toxicity

Patient without cardiac history:

Hemoglobin <10 g/dL:

Children ≥3 years: Oral capsules, oral solution:

First reduction: Decrease to 12 mg/kg/day

Second reduction: Decrease to 8 mg/kg/day

Children ≥5 years: Oral tablets (Copegus®):

23-33 kg: Decrease dose to 200 mg daily (in the morning)

34-59 kg: Decrease dose to 400 mg daily (200 mg in the morning and evening)

≥60 kg: Decrease dose to 600 mg daily (200 mg in the morning and 400 mg in the evening)

Adults:

Oral capsules, oral solution:

First reduction: ≤105 kg: Decrease by 200 mg daily; >105 kg: Decrease by 400 mg daily Second reduction: Decrease by an additional 200 mg daily (not weight- based)

Oral tablets: Decrease dose to 600 mg daily (200 mg in the morning, 400 mg in the evening)

Hemoglobin <8.5 g/dL: Children and Adults: Oral capsules, solution, tablets: Permanently discontinue treatment.

WBC <1000 mm3, neutrophils <500 mm3: Children and Adults: Oral capsules, solution: Permanently discontinue treatment.

Platelets <50 x 109/L: Children: Oral capsules, solution: Permanently discontinue treatment.

Platelets <25 x 109/L: Adults: Oral capsules, solution: Permanently discontinue treatment.

Creatinine (serum) >2 mg/dL: Children: Oral capsules, solution: Permanently discontinue treatment.

Patient with cardiac history:

Hemoglobin has decreased ≥2 g/dL during any 4-week period of treatment:

Children: Oral capsules, solution: Weekly evaluation and hematologic testing

Children ≥5 years: Oral tablets (Copegus®):

23-33 kg: Decrease dose to 200 mg daily (in the morning)

34-59 kg: Decrease dose to 400 mg daily (200 mg in the morning and evening)

≥60 kg: 600 mg daily (200 mg in the morning, 400 mg in the evening)

Hemoglobin has decreased >2 g/dL during any 4-week period of treatment: Adults:

Oral capsules, solution: Decrease dose by 200 mg daily

Oral tablets: 600 mg (200 mg in the morning, 400 mg in the evening)

Hemoglobin <12 g/dL after 4 weeks of reduced dose: Children and Adults: Oral capsules, solution, tablets: Permanently discontinue treatment.

Hemoglobin <8.5 g/dL: Children and Adults: Oral capsules, solution, tablets: Permanently discontinue treatment.

WBC <1000 mm3, neutrophils <500 mm3: Children and Adults: Oral capsules, solution: Permanently discontinue treatment.

Platelets <50 x 109/L: Children: Oral capsules, solution: Permanently discontinue treatment.

Platelets <25 x 109/L: Adults: Oral capsules, solution: Permanently discontinue treatment.

Creatinine (serum) >2 mg/dL at any time during therapy: Children: Oral capsules, solution: Permanently discontinue treatment.

Dosage Forms: U.S.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Capsule, oral: 200 mg

Rebetol®: 200 mg

Ribasphere®: 200 mg

Powder for solution, for nebulization:

Virazole®: 6 g [reconstituted product contains ribavirin 20 mg/mL]

Solution, oral:

Rebetol®: 40 mg/mL (100 mL) [contains propylene glycol, sodium benzoate; bubblegum flavor]

Tablet, oral: 200 mg

Copegus®: 200 mg

Ribasphere®: 200 mg, 400 mg, 600 mg

Tablet, oral [dose-pack]:

Ribasphere® RibaPak® 600: 200 mg AM dose, 400 mg PM dose (14s, 56s)

Ribasphere® RibaPak® 800: 400 mg AM dose, 400 mg PM dose (14s, 56s)

Ribasphere® RibaPak® 1000: 600 mg AM dose, 400 mg PM dose (14s, 56s)

Ribasphere® RibaPak® 1200: 600 mg AM dose, 600 mg PM dose (14s, 56s)

Generic Equivalent Available: U.S.

Yes: Capsule, tablet

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Copegus®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088576.pdf,

Rebetol®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089017.pdf

Ribasphere®: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm111342.pdf

Administration

Inhalation: Ribavirin should be administered in well-ventilated rooms (at least 6 air changes/hour). In mechanically-ventilated patients, ribavirin can potentially be deposited in the ventilator delivery system depending on temperature, humidity, and electrostatic forces; this deposition can lead to malfunction or obstruction of the expiratory valve, resulting in inadvertently high positive end-expiratory pressures. The use of one-way valves in the inspiratory lines, a breathing circuit filter in the expiratory line, and frequent monitoring and filter replacement have been effective in preventing these problems. Solutions in SPAG-2 unit should be discarded at least every 24 hours and when the liquid level is low before adding newly reconstituted solution. Should not be mixed with other aerosolized medication.

Oral: Administer concurrently with interferon alfa injection. Capsule should not be opened, crushed, chewed, or broken. Use oral solution for children <47 kg, or those who cannot swallow capsules. Capsule, solution, tablet: Administer with food.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH, 2012).

Compatibility

Inhalation: Should not be mixed with other aerosolized medication.

Use

Inhalation: Treatment of hospitalized infants and young children with respiratory syncytial virus (RSV) infections; specially indicated for treatment of severe lower respiratory tract RSV infections in patients with an underlying compromising condition (prematurity, cardiopulmonary disease, or immunosuppression)

Oral capsule: In combination with interferon alfa 2b (pegylated or nonpegylated) injection for the treatment of chronic hepatitis C in interferon alfa-naive or experienced-patients with compensated liver disease. Patients likely to fail retreatment after a prior failed course include previous nonresponders, those who received previous pegylated interferon treatment, patients who have significant bridging fibrosis or cirrhosis, or those with genotype 1 infection.

Oral solution: In combination with interferon alfa-2b (pegylated or nonpegylated) injection for the treatment of chronic hepatitis C in interferon alfa-naive or experienced patients ≥3 years of age with compensated liver disease. Patients likely to fail retreatment after a prior failed course include previous nonresponders, those who received previous pegylated interferon treatment, patients who have significant bridging fibrosis or cirrhosis, or those with genotype 1 infection.

Oral tablet: In combination with peginterferon alfa-2a (Pegasys®) injection for the treatment of chronic hepatitis C in patients with compensated liver disease who were previously untreated with alpha interferons, and in adult chronic hepatitis C patients coinfected with HIV.

Use - Unlabeled

Inhalation: Treatment for RSV in adult hematopoietic stem cell or heart/lung transplant recipients

Used in other viral infections including influenza A and B and adenovirus

Medication Safety Issues Sound-alike/look-alike issues:

Ribavirin may be confused with riboflavin, rifampin, Robaxin®

Adverse Reactions Significant

Inhalation:

1% to 10%:

Central nervous system: Fatigue, headache, insomnia

Gastrointestinal: Nausea, anorexia

Hematologic: Anemia <1% (Limited to important or life-threatening): Hypotension, cardiac arrest, digitalis toxicity, conjunctivitis, mild bronchospasm, worsening of respiratory function, apnea

Note: Incidence of adverse effects (approximate) in healthcare workers: Headache (51%); conjunctivitis (32%); rhinitis, nausea, rash, dizziness, pharyngitis, and lacrimation (10% to 20%); bronchospasm and/or chest pain (case reports in individuals with underlying airway disease)

Oral (all adverse reactions are documented while receiving combination therapy with alfa interferons; percentages as reported in adults unless noted, most common pediatric adverse reactions were similar to adults); asterisked (*) percentages are those similar to interferon therapy alone:

>10%:

Central nervous system: Fatigue (60% to 70% [30% in pediatric patients])*, headache (43% to 66%)*, fever (32% to 55%)*, insomnia (26% to 41% [9% in pediatric patients]), depression (20% to 36%)*, irritability (23% to 33%), dizziness (14% to 26%), impaired concentration (10% to 21%)*, emotional lability (7% to 12%)*

Dermatologic: Alopecia (27% to 36% [17% in pediatric patients]), pruritus (13% to 29% [11% in pediatric patients]), rash (5% to 28%), dry skin (10% to 24%), dermatitis (≤16%)

Endocrine and metabolic: Growth suppression (pediatric) percentile decrease (≥15 percentiles: weight 43%; height 25%), hyperuricemia (33% to 38%)

Gastrointestinal: Nausea (25% to 47% [18% in pediatric patients]), anorexia (21% to 32%), weight decrease (10% to 29%), vomiting (9% to 25%)*, diarrhea (10% to 22%), dyspepsia (6% to 16%), abdominal pain (8% to 13%), xerostomia (≤12%), RUQ pain (≤12%)

Hematologic: Leukopenia (6% to 45%), neutropenia (8% to 42%; grade 4: 2% to 11%; 40% with HIV coinfection), hemoglobin decreased (11% to 35%), anemia (11% to 17%), thrombocytopenia (<1% to 15%), lymphopenia (12% to 14%), hemolytic anemia (10% to 13%)

Hepatic: Bilirubin increase (10% to 32%)

Neuromuscular & skeletal: Myalgia (40% to 64% [17% in pediatric patients])*, rigors (25% to 48%), arthralgia (22% to 34%)*, musculoskeletal pain (19% to 28% [35% in pediatric patients])

Respiratory: Upper respiratory tract infection (60% in pediatric patients), dyspnea (13% to 26%), cough (7% to 23%), pharyngitis (≤13%), sinusitis (≤12%)*

Miscellaneous: Flu-like syndrome (13% to 18% [up to 91% in pediatric patients])*, viral infection (≤12%), diaphoresis (≤11%)

1% to 10%:

Cardiovascular: Chest pain (5% to 9%)*, flushing (≤4%)

Central nervous system: Pain (≤10%), mood alteration (≤6%; 9% with HIV coinfection), agitation (5% to 8%), nervousness (6%)*, memory impairment (≤6%), malaise (≤6%), suicidal ideation (adolescents: 2%; adults: 1%) Dermatologic: Eczema (4% to 5%)

Endocrine & metabolic: Menstrual disorder (≤7%), hypothyroidism (≤5%)

Gastrointestinal: Taste perversion (4% to 9%), constipation (5%)

Hepatic: Hepatomegaly (4%), transaminases increased (1% to 3%), hepatic decompensation (2% with HIV coinfection)

Neuromuscular & skeletal: Weakness (9% to 10%), back pain (5%)

Ocular: Blurred vision (≤6%), conjunctivitis (≤5%)

Respiratory: Rhinitis (≤8%), exertional dyspnea (≤7%)

Miscellaneous: Fungal infection (≤6%), bacterial infection (3% to 5%)

<1% (Limited to important or life-threatening): Aggression, angina, anxiety, aplastic anemia, arrhythmia; autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis); bone marrow suppression, cerebral hemorrhage, cholangitis, colitis, coma, corneal ulcer, dehydration, diabetes mellitus, drug abuse relapse/overdose, exfoliative dermatitis, fatty liver, hearing impairment/loss, gastrointestinal bleeding, gout, hallucination, hepatic dysfunction, hyper-/hypothyroidism, hypersensitivity (including anaphylaxis, angioedema, bronchoconstriction, and urticaria), macular edema, myositis, optic neuritis, papilledema, pancreatitis, peptic ulcer, peripheral neuropathy, pneumonitis, psychosis, psychotic disorder, pulmonary dysfunction, pulmonary embolism, pulmonary infiltrates, pure red cell aplasia, retinal artery/vein thrombosis, retinal detachment, retinal hemorrhage, retinopathy, sarcoidosis exacerbation; skin reactions (erythema multiforme, exfoliative dermatitis, urticaria, vesiculobullous eruptions); Stevens-Johnson syndrome, suicide, thrombotic thrombocytopenic purpura, thyroid function test abnormalities; transplant rejection (kidney, liver); vision loss

Note: Incidence of headache, fever, suicidal ideation, and vomiting are higher in children.

Contraindications Inhalation: Hypersensitivity to ribavirin or any component of the formulation; women who are pregnant or may become pregnant

Oral formulations: Hypersensitivity to ribavirin or any component of the formulation; women who are pregnant or may become pregnant; males whose female partners are pregnant; patients with hemoglobinopathies (eg, thalassemia major, sickle cell anemia); patients with autoimmune hepatitis; concomitant use with didanosine

Ribasphere® capsules and Rebetol® capsules/solution: Additional contraindications:

Patients with a Clcr<50 mL/minute

Oral combination therapy: Refer to individual monographs for Interferon Alfa-2b (Intron® A), Peginterferon Alfa-2b, and Peginterferon Alfa-2a (Pegasys®) for additional contraindication information.

Warnings/Precautions

Concerns related to adverse effects:

• Hemolytic anemia: [U.S. Boxed Warning]: Hemolytic anemia is the primary clinical toxicity of oral therapy; anemia associated with ribavirin may worsen underlying cardiac disease and lead to fatal and nonfatal myocardial infarctions. Avoid use in patients with significant/unstable cardiac disease. Anemia usually occurs within 1-2 weeks of therapy initiation; observed in ~10% to 13% of patients when alfa interferons were combined with ribavirin. Assess cardiac function before initiation of therapy. If patient has underlying cardiac disease, assess electrocardiogram prior to and periodically during treatment. If any deterioration in cardiovascular status occurs, discontinue therapy. Use caution in patients with baseline risk of severe anemia. Assess hemoglobin and hematocrit at baseline and, at minimum, weeks 2 and 4 of therapy since initial drop may be significant. Patients with renal dysfunction and/or those >50 years of age should be carefully assessed for development of anemia.

Disease-related concerns:

• Hepatic impairment: Risk of hepatic decompensation in chronic hepatitis C patients treated with combination therapy; monitor hepatic function closely and discontinue therapy immediately if evidence of hepatic decompensation is observed.

• Hepatitis C: Appropriate use: [U.S. Boxed Warning]: Ribavirin monotherapy is not effective for chronic hepatitis C infection and should not be used alone for hepatitis C.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment or discontinuation may be required.

Concurrent drug therapy issues:

Combination therapy with alfa interferons:

• Autoimmune/infectious disorders: Have occurred with combination therapy; use with caution in patients with autoimmune disease or severe infection.

• Bone marrow suppression: Pancytopenia has occurred with combination therapy and concomitant use of azathioprine; onset occurs within 3-7 weeks; discontinue combination therapy and azathioprine if occurs; may be reversible (usually within 4-6 weeks).

• Dental and periodontal disorders: Have been reported with combination therapy; patients should be instructed to brush teeth twice daily and have regular dental exams. Xerostomia may contribute to and/or exacerbate dental disorders.

• Dermatologic reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome and exfoliative dermatitis have been reported (rarely) with combination therapy; discontinue immediately with signs or symptoms of severe skin reactions.

• Diabetes: Has occurred with combination therapy; monitor blood sugars closely.

• Hypersensitivity reactions: Acute hypersensitivity reactions (eg, anaphylaxis, angioedema, bronchoconstriction, and urticaria) have been observed (rarely) with combination therapy; discontinue immediately with signs or symptoms of severe hypersensitivity reactions.

• Ophthalmologic disorders: Serious disorders (eg, retinopathy, macular edema, retinal artery/vein thrombosis, optic neuritis, retinal detachment) have occurred with combination therapy. All patients require an eye exam at baseline; those with pre- existing ophthalmologic disorders (eg, diabetic or hypertensive retinopathy) require periodic follow up. Discontinue therapy in patients with new or worsening ophthalmologic disorders. • Pancreatitis: Has occurred with combination therapy; interrupt therapy if pancreatitis is suspected and discontinue if confirmed.

• Psychiatric disorders: Severe psychiatric events have occurred including depression and suicidal behavior during combination therapy. Suicidal ideation or attempts occurred more often in pediatric patients versus reports in adults during treatment and off- therapy follow- up (2.4% vs 1%). Avoid use in patients with a psychiatric history; discontinue if severe psychiatric symptoms occur.

• Pulmonary events: Pulmonary symptoms (eg, dyspnea, pulmonary infiltrates, pneumonitis, pneumonia [rarely fatal]) have been associated with combination therapy; use with caution in patients with pulmonary disease, including sarcoidosis (exacerbation reported).

Special populations:

• Elderly: Use with caution in the elderly; may be more susceptible to adverse effects such as anemia. Monitor renal function closely.

• Pediatric: In combination therapy with alfa interferons, ribavirin may cause a reduction in growth velocity in pediatric patients for the length of treatment. Delay in weight and height increases have been noted in children treated with combination therapy. In clinical studies, decreases were noted in weight and height for age z-scores and normative growth curve percentiles. At two-year follow up after treatment, most children had returned to their baseline normative growth curve percentiles; however, a small percentage did not. Growth should be closely monitored in pediatric patients during therapy and post-treatment until growth catch up has occurred.

• Pregnancy: [U.S. Boxed Warning]: Significant teratogenic effects have been observed in all animal studies. A negative pregnancy test is required before initiation and monthly thereafter. Avoid pregnancy in female patients and female partners of male patients, during therapy, and for at least 6 months after treatment; two forms of contraception should be used.

Dosage form specific issues:

• Inhalation: [U.S. Boxed Warning]: Use with caution in patients requiring assisted ventilation because precipitation of the drug in the respiratory equipment may interfere with safe and effective patient ventilation; sudden deterioration of respiratory function has been observed;monitor carefully in patients with COPD and asthma for deterioration of respiratory function. Ribavirin is potentially mutagenic, tumor-promoting, and gonadotoxic. Although anemia has not been reported with inhalation therapy, consider monitoring for anemia 1-2 weeks post- treatment. Pregnant healthcare workers may consider unnecessary occupational exposure; ribavirin has been detected in healthcare workers' urine. Healthcare professionals or family members who are pregnant (or may become pregnant) should be counseled about potential risks of exposure and counseled about risk reduction strategies.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH, 2012).

Other warnings/precautions:

• Appropriate use: Safety and efficacy have not been established in patients who have failed other alfa interferon therapy, received organ transplants, or been coinfected with hepatitis B or HIV (ribavirin tablets [Copegus®, Ribasphere®] may be used in HIV coinfected patients unless CD4+ cell count is <100 cells/microliter and HIV-1 RNA <5000 cells/mm3). Hemoglobin at initiation must be ≥12 g/dL (women) or ≥13 g/dL (men) in CHC monoinfected patients and ≥11 g/dL (women) or ≥12 g/dL (men) in CHC and HIV coinfected patients. Oral ribavirin should not be used for adenovirus, RSV, influenza or parainfluenza infections; ribavirin inhalation is approved for severe RSV infection in children.

Metabolism/Transport Effects

None known.

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

AzaTHIOprine: Ribavirin may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients extra closely for signs/symptoms of myelosuppression. Risk D: Consider therapy modification

Didanosine: Ribavirin may enhance the adverse/toxic effect of Didanosine. Ribavirin may increase serum concentrations of the active metabolite(s) of Didanosine. Risk X: Avoid combination

Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid anti- influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Risk D: Consider therapy modification

Interferons (Alfa): May enhance the adverse/toxic effect of Ribavirin. Hemolytic anemia has been observed. Risk C: Monitor therapy

Reverse Transcriptase Inhibitors (Nucleoside): Ribavirin may enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Lactic acidosis may occur. Risk D: Consider therapy modification

Zidovudine: May enhance the adverse/toxic effect of Ribavirin. Specifically, the risk/severity of anemia may be increased. Management: Due to significantly increased risk of anemia, consider even closer monitoring for anemia than routinely recommended for ribavirin. Alternative therapies should be considered when clinically possible, particularly for patients with other risk factors. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions

Food: Oral: High-fat meal increases the AUC and Cmax. Management: Capsule (in combination with peginterferon alfa-2b) and tablet should be administered with food. Other dosage forms and combinations should be taken consistently in regards to food.

Pregnancy Risk Factor

X (show table) Pregnancy Implications

[U.S. Boxed Warning]: Significant teratogenic effects have been observed in all animal studies at ~0.01 times the maximum recommended daily human dose. Use is contraindicated in pregnancy. Negative pregnancy test is required before initiation and monthly thereafter. Avoid pregnancy in female patients and female partners of male patients during therapy by using two effective forms of contraception; continue contraceptive measures for at least 6 months after completion of therapy. If patient or female partner becomes pregnant during treatment, she should be counseled about potential risks of exposure. If pregnancy occurs during use or within 6 months after treatment, report to the ribavirin pregnancy registry (800-593-2214).

Lactation

Excretion in breast milk unknown/not recommended

Dietary Considerations

Capsules, solution, and tablets should be taken with food.

Pricing: U.S. (Medi-Span®)

Capsules (Rebetol Oral)

200 mg (70): $741.74

Capsules (Ribasphere Oral)

200 mg (70): $328.44

Capsules (Ribavirin Oral)

200 mg (56): $556.29

Misc (RibaPak Oral)

200 & 400 mg (14): $219.14

Solution (Rebetol Oral)

40 mg/mL (100 mL): $232.80

Solution (reconstituted) (Virazole Inhalation)

6 g (1): $6212.37

Tablets (Copegus Oral)

200 mg (168): $3305.38

Tablets (RibaPak Oral)

400 mg (14): $230.67

400 & 600 mg (14): $288.34

600 mg (14): $346.01

Tablets (Ribasphere Oral)

200 mg (168): $474.00

400 mg (56): $922.68 600 mg (56): $1384.02

Tablets (Ribavirin Oral)

200 mg (168): $1390.00

Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

Monitoring Parameters

Inhalation: Respiratory function, hemoglobin, reticulocyte count, CBC with differential, I & O

Oral: For combination treatment: pretreatment hematological and biochemical tests are recommended for all patients; pregnancy screening (if woman of childbearing age) and ECG (if preexisting cardiac abnormalities) are also recommended. In adults, hematologic tests should be at treatment weeks 2 and 4, biochemical tests at week 4, TSH at week 12, and pregnancy tests monthly during and for 6 months after treatment discontinuation.

In pediatric clinical studies, hematologic and biochemical assessments were made at weeks 1, 3, 5 and 8, then every 4 weeks thereafter.

Baseline values used in adult clinical trials:

Platelet count ≥90,000/mm3 (75,000/mm3 for cirrhosis or 70,000/mm3 for coinfection with HIV)

ANC ≥1500/mm3

Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men (11 g/dL for HIV coinfected women and 12 g/dL for HIV coinfected men)

TSH and T4 within normal limits or adequately controlled

CD4+ cell count ≥200 cells/microL or CD4+ cell count 100-200 cells/microL and HIV-1 RNA <5000 copies/mL for coinfection with HIV

Serum HCV RNA (pretreatment, week 12 and week 24, and 24 weeks after completion of therapy). Note:Discontinuation of therapy may be considered after 12 weeks in patients with HCV (genotypes 1,4) who fail to achieve an early virologic response (EVR) (defined as ≥2-log decrease in HCV RNA compared to pretreatment) or after 24 weeks with detectable HCV RNA. Treat patients with HCV (genotypes 2,3) for 24 weeks (if tolerated) and then evaluate HCV RNA levels (Ghany, 2009).

Pretreatment and monthly pregnancy test up to 6 months following discontinuation of therapy for women of childbearing age; pretreatment ECG in patients with pre-existing cardiac disease; dental exams; ophthalmic exam pretreatment (all patients) and periodically for those with pre-existing ophthalmologic disorders. In pediatric patients, monitor growth closely during and after treatment.

Reference Range

Rapid virological response (RVR): Absence of detectable HCV RNA after 4 weeks of treatment

Early viral response (EVR): ≥2-log decrease in HCV RNA after 12 weeks of treatment End of treatment response (ETR): Absence of detectable HCV RNA at end of the recommended treatment period

Sustained treatment response (STR) or sustained virologic response (SVR): Absence of HCV RNA in the serum 6 months following completion of full treatment course

International Brand Names

 Copegus (AR, AT, BE, BG, CH, CO, CZ, DE, DK, EC, EE, FI, FR, GB, GR, HK, IE, IL, IT, MX, NL, NO, NZ, PL, PT, SE, TH, UY);

 Desiken (MX);

 Hepaviral (ID);

 Probirina (MX);

 Rebetol (AT, AU, BE, BG, CH, CN, CZ, DE, DK, DO, EE, ES, FI, FR, GB, GR, ID, IE, IL, IT, MT, MY, NL, NO, NZ, PA, PH, PL, PT, RU, SE, SG, SK, TH, TR, VE);

 Ribavin (IN);

 Robatrol (TW);

 Robavin (KP);

 Rui Di (CL);

 Trivorin (MX);  Vibuzol (AR);

 Vilona (MX);

 Viramid (IT, KP);

 Virazide (AU, MX, PK);

 Virazin (KP);

 Virazole (AE, BE, BH, BR, CR, CY, EG, GB, GT, HN, IQ, IR, JO, KW, LB, LY, NI, OM, QA, SA, SE, SV, SY, YE);

 Zyverin (TW)

Mechanism of Action

Inhibits replication of RNA and DNA viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis

Pharmacodynamics/Kinetics

Absorption: Inhalation: Systemic; dependent upon respiratory factors and method of drug delivery; maximal absorption occurs with the use of aerosol generator via endotracheal tube; highest concentrations in respiratory tract and erythrocytes

Distribution: Oral capsule: Single dose: Vd: 2825 L; distribution significantly prolonged in the erythrocyte (16-40 days), which can be used as a marker for intracellular metabolism

Protein binding: Oral: None

Metabolism: Hepatically and intracellularly (forms active metabolites); may be necessary for drug action

Bioavailability: Oral: 64%

Half-life elimination, plasma:

Children: Inhalation: 6.5-11 hours

Adults: Oral:

Capsule, single dose (Rebetol®, Ribasphere®): 24 hours in healthy adults, 44 hours with chronic hepatitis C infection (increases to ~298 hours at steady state)

Tablet, single dose (Copegus®): ~120-170 hours

Time to peak, serum: Inhalation: At end of inhalation period; Oral capsule: Multiple doses: 3 hours; Tablet: 2 hours

Excretion: Inhalation: Urine (40% as unchanged drug and metabolites); Oral capsule: Urine (61%), feces (12%) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

1. American Academy of Pediatrics Committee on Infectious Diseases, “Reassessment of the Indications for Ribavirin Therapy in Respiratory Syncytial Virus Infections,” Pediatrics, 1996, 97(1):137-40. [PubMed8545210] 2. American Academy of Pediatrics Committee on Infectious Diseases, “Use of Ribavirin in the Treatment of Respiratory Syncytial Virus Infection,” Pediatrics, 1993, 92(3):501- 4. [PubMed 8361820] 3. Barry M, Russi M, Armstrong L, et al, “Brief Report: Treatment of a Laboratory-Acquired Saria Virus Infection,” N Engl J Med, 1995, 333(5):294-6. [PubMed 7596373] 4. Boeckh M, Englund J, Li Y, et al, “Randomized Controlled Multicenter Trial of Aerosolized Ribavirin For Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic Cell Transplant Recipients,”Clin Infect Dis, 2007, 44(2):245-9. [PubMed 17173225] 5. Chemaly RF, Ghosh S, Bodey GP, et al, “Respiratory Viral Infections in Adults With Hematologic Malignancies and Human Stem Cell Transplant Recipients: A Retrospective Study at a Major Cancer Center,” Medicine (Baltimore), 2006, 85(5):278-87. [PubMed 16974212] 6. Davis GL, Esteban-Mur R, Rustgi V, et al, “Interferon Alfa-2b Alone or in Combination With Ribavirin for the Treatment of Relapse of Chronic Hepatitis C. International Hepatitis Interventional Therapy Group,” N Engl J Med, 1998, 339(21):1493-9. [PubMed 9819447] 7. Dienstag JL and McHutchinson JG, “American Gastroenterological Association Medical Position Statement on the Management of Hepatitis C,” Gastroenterology, 2006, 130(1):225- 30. [PubMed 16401485] 8. Englund JA, Piedra PA, Ahn YM, et al, “High-Dose, Short-Duration Ribavirin Aerosol Therapy Compared With Standard Ribavirin Therapy in Children With Suspected Respiratory Syncytial Virus Infection,” J Pediatr, 1994, 125:635-41. [PubMed 7931890] 9. Ghany MG, Nelson DR, Strader DB, et al, “An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases,”Hepatology, 2011, 54(4):1433-44. [PubMed 21898493] 10. Ghany MG, Strader DB, Thomas DL, et al, “Diagnosis, Management And Treatment Of Hepatitis C: An Update,” Hepatology, 2009, 49(4):1335-74. [PubMed 19330875] 11. Hoofnagle JH and Seeff LB,”Peginterferon and Ribavirin for Chronic Hepatitis C,” N Engl J Med, 2006, 355(23):2444-51. [PubMed 17151366] 12. Lauer GM and Walker BD, “Hepatitis C Virus Infection,” N Engl J Med, 2001, 345(1):41- 52. [PubMed11439948] 13. Liu V, Dhillon GS, and Weill D, “A Multi-Drug Regimen for Respiratory Syncytial Virus and Parainfluenza Virus Infections in Adult Lung and Heart-Lung Transplant Recipients,” Transp Infect Dis, 2010, 12(1):38-44.[PubMed 19761558] 14. McHutchison JG, Gordon SC, Schiff ER, et al, “Interferon Alfa-2b Alone or in Combination With Ribavirin as Initial Treatment for Chronic Hepatitis C. Hepatitis Interventional Therapy Group,” N Engl J Med, 1998, 339(21):1485-92. [PubMed 9819446] 15. Meert KL, Sarnaik AP, Gelmini MJ, et al, “Aerosolized Ribavirin in Mechanically Ventilated Children With Respiratory Syncytial Virus Lower Respiratory Tract Disease: A Prospective, Double-Blind, Randomized Trial,” Crit Care Med, 1994, 22(4):566-72. [PubMed 8143465] 16. National Institute for Occupational Safety and Health (NIOSH), "NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012." Available at http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. Accessed January 21, 2013. 17. Nicholson KG, “Properties of Antiviral Agents,” Lancet, 1984, 2(8401):503-6 and 2(8402):562-4. 18. Ottolini MG and Hemming VG, “Prevention and Treatment Recommendations for Respiratory Syncytial Virus Infection. Background and Clinical Experience 40 Years After Discovery,” Drugs, 1997, 54(6):867-84.[PubMed 9421694] 19. "PEDS-C: Pegylated Interferon +/- Ribavirin for Children With Hepatitis C," NCT0010065, updated November 2012. Available at http://clinicaltrials.gov/ct2/show/NCT00100659 20. Schwarz KB, Gonzalez-Peralta RP, Murray KF, et al, “The Combination of Ribavirin and Peginterferon is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C,”Gastroenterology, 2011, 140(2):450-8. [PubMed 21036173] 21. Smith DW, Frankel LR, Mathers LH, et al, “A Controlled Trial of Aerosolized Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory Syncytial Virus Infection,” N Engl J Med, 1991, 325(1):24-9.[PubMed 1904551] 22. Sokal E, Bourgois A, Stephenne X, et al, “Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C Virus Infection in Children and Adolescents,” J Hepatol, 2010, 52(6):827- 31. [PubMed 20400194] 23. Van Bever HP, Desager KS, Van Hoeck K, et al, “Water Intoxication After Nebulised Tribavirin,” Lancet, 1995, 345(8947):451.

Topic 9860 Version 42.0

Chlorpheniramine: Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Chlorpheniramine: Patient drug information" and see "Chlorpheniramine: Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table) Brand Names: U.S.

 Aller-Chlor [OTC];

 Allergy 4 Hour [OTC];

 Allergy Relief [OTC];

 Allergy [OTC];

 Allergy-Time [OTC];

 Chlor-Trimeton Allergy [OTC];

 Chlor-Trimeton [OTC];

 Chlorphen [OTC];

 Ed ChlorPed;

 Ed Chlorped Jr [OTC];

 Ed ChlorPed [OTC];

 Ed-Chlor-Tan;

 Ed-Chlortan [OTC];

 Pharbechlor [OTC]

Brand Names: Canada

 Chlor-Tripolon®;

 Novo-Pheniram

Pharmacologic Category

 Alkylamine Derivative;

 Histamine H;1 Antagonist

 Histamine H1 Antagonist, First Generation

Dosing: Adult

Allergic symptoms, allergic rhinitis: Oral: Chlorpheniramine maleate:

Immediate release: 4 mg every 4-6 hours; do not exceed 24 mg/24 hours

Extended release: 12 mg every 12 hours; do not exceed 24 mg/24 hours

Dosing: Pediatric

(For additional information see "Chlorpheniramine: Pediatric drug information")

Allergic symptoms, allergic rhinitis: Oral: Chlorpheniramine maleate:

Immediate release:

Children 2-5 years: 1 mg every 4-6 hours; do not exceed 6 mg/24 hours Children 6-11 years: 2 mg every 4-6 hours; do not exceed 12 mg/24 hours

Children ≥12 years: Refer to adult dosing.

Extended release: Children ≥12 years: Refer to adult dosing.

Dosage Forms: U.S.

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

Liquid, Oral, as maleate:

Ed ChlorPed: 2 mg/mL (60 mL) [contains fd&c red #40, propylene glycol, saccharin sodium, sodium benzoate; cotton candy flavor]

Suspension, Oral, as tannate:

Ed ChlorPed: 2 mg/mL (60 mL) [contains aspartame, methylparaben, propylene glycol, propylparaben; cotton candy flavor]

Syrup, Oral, as maleate:

Aller-Chlor: 2 mg/5 mL (118 mL) [fruit flavor]

Chlor-Trimeton: 2 mg/5 mL (120 mL) [contains alcohol, usp]

Ed Chlorped Jr: 2 mg/5 mL (118 mL, 473 mL) [alcohol free, sugar free; contains fd&c red #40, methylparaben, propylene glycol, propylparaben; cherry flavor]

Tablet, Oral, as maleate:

Aller-Chlor: 4 mg [scored]

Allergy: 4 mg

Allergy: 4 mg [contains fd&c yellow #10 (quinoline yellow)]

Allergy: 4 mg [contains fd&c yellow #10 aluminum lake]

Allergy: 4 mg [scored; contains fd&c yellow #10 aluminum lake]

Allergy 4 Hour: 4 mg [contains fd&c yellow #10 (quinoline yellow)]

Allergy Relief: 4 mg [contains fd&c yellow #10 aluminum lake]

Allergy-Time: 4 mg [contains fd&c yellow #10 aluminum lake]

Chlor-Trimeton: 4 mg [scored]

Chlorphen: 4 mg [scored; contains fd&c yellow #10 (quinoline yellow)]

Ed-Chlortan: 4 mg [scored; contains fd&c yellow #10 aluminum lake]

Pharbechlor: 4 mg

Generic: 4 mg

Tablet, Oral, as tannate:

Ed-Chlor-Tan: 8 mg [scored]

Tablet Extended Release, Oral, as maleate: Chlor-Trimeton Allergy: 12 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Chlor-Trimeton Allergy: 12 mg [contains fd&c yellow #6 (sunset yellow), fd&c yellow #6 aluminum lake]

Generic: 12 mg

Generic Equivalent Available: U.S.

May be product dependent

Administration

May be administered with food or water. Timed release oral forms are to be swallowed whole, not crushed or chewed.

Use

Perennial and seasonal allergic rhinitis and other allergic symptoms including urticaria

Medication Safety Issues Sound-alike/look-alike issues:

Chlor-Trimeton® may be confused with Chloromycetin® BEERS Criteria medication:

This drug may be potentially inappropriate for use in geriatric patients (Quality of evidence - moderate; Strength of recommendation - strong).

Adverse Reactions Significant

>10%:

Central nervous system: Slight to moderate drowsiness

Respiratory: Thickening of bronchial secretions

1% to 10%:

Central nervous system: Headache, excitability, fatigue, nervousness, dizziness

Gastrointestinal: Nausea, xerostomia, diarrhea, abdominal pain, appetite increase, weight gain

Genitourinary: Urinary retention

Neuromuscular & skeletal: Arthralgia, weakness

Ocular: Diplopia

Renal: Polyuria

Respiratory: Pharyngitis

Contraindications

Hypersensitivity to chlorpheniramine maleate or any component of the formulation; narrow- angle glaucoma; bladder neck obstruction; symptomatic prostate hypertrophy; during acute asthmatic attacks; stenosing peptic ulcer; pyloroduodenal obstruction. Avoid use in premature and term newborns due to possible association with SIDS. Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (including hypertension and ischemic heart disease).

• Increased intraocular pressure: Use with caution in patients with increased intraocular pressure.

• Prostatic hyperplasia/urinary obstruction: Use with caution in patients with prostatic hyperplasia and/or GU obstruction.

• Respiratory disease: Use with caution in patients with asthma or other chronic breathing disorders.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• Elderly: Avoid use of this potent anticholinergic agent due to increased risk of confusion, dry mouth, constipation, and other anticholinergic effects; clearance decreases in patients of advanced age (Beers Criteria).

• Pediatrics: Antihistamines may cause excitation in young children. Not for OTC use in children <2 years of age.

Metabolism/Transport Effects

Substrate of CYP2D6 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity.Risk D: Consider therapy modification

Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergics. Risk X: Avoid combination Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Risk D: Consider therapy modification

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Risk C: Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of CNS depressants used in combination with buprenorphine. Consider avoiding other CNS depressants in patients thought to be at high risk of buprenorphine overuse or self-injection. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Hyaluronidase: Antihistamines may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergics. Risk X: Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Risk C: Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract.Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Tiotropium: Anticholinergics may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions

Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.

Pregnancy Implications

Maternal chlorpheniramine use has generally not resulted in an increased risk of birth defects. Antihistamines are recommended for the treatment of rhinitis, urticaria, and pruritus with rash in pregnant women (although second generation antihistamines may be preferred). Antihistamines are not recommended for treatment of pruritus associated with intrahepatic cholestasis in pregnancy.

Breast-Feeding Considerations

Information specific to the use of chlorpheniramine is limited. Antihistamines may decrease maternal serum prolactin concentrations when administered prior to the establishment of nursing.

Dietary Considerations

May be taken with food or water. Some products may contain phenylalanine.

Pricing: U.S. (Medi-Span®)

Liquid (Ed ChlorPed Oral)

2 mg/mL (60 mL): $21.00

Suspension (Ed ChlorPed Oral)

2 mg/mL (60 mL): $21.00

Syrup (Chlor-Trimeton Oral)

2 mg/5 mL (120 mL): $4.82

Tablet, controlled release (Chlor-Trimeton Allergy Oral)

12 mg (10): $4.62

Tablet, controlled release (Chlorpheniramine Maleate ER Oral)

12 mg (24): $15.00

Tablets (Chlor-Trimeton Oral)

4 mg (24): $4.62

Tablets (Chlorpheniramine Maleate Oral)

4 mg (100): $2.25

Tablets (Ed-Chlor-Tan Oral)

8 mg (100): $60.00 Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

International Brand Names

 Ahiston (IL);

 Alerfin (PY);

 Alergidryl (AR);

 Alergitrat (AR);

 Aller (MY);  Allerfin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Allergex (ZA);

 Allergyl (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Allermin (SG, TW);

 Analerg (UY);

 Antadex-H (MX);

 Antamin (MY, PH, SG);  Bregamin (MX);

 Cadistin (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Chloramine (MY, SG);

 Chlorpheniramine DHA (HK);

 Chlorpheno (TH);  Chlorphenon (ID);

 Chlorpyrimine (HK, MY, TH);

 Chlortrimeton (ZA);

 Clorfam (CO);

 Cloro Trimeton (AR);

 Cloro-Trimeton (MX);

 Cloroalergan (PE);

 Clorotrimeton (PE, VE);

 Co-Timine (TW);

 Cohistan (ID);

 Com-Trimeton (TW);  Derimeton (MX);

 Histafen (NZ);

 Histal (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT);

 Histat (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Histatapp (TH);

 Histavil (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Histin (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Istamex (GR);  Niramine (TW);

 Orphen (ID);

 Pirafene (BG);

 Piriton (AE, BB, BH, BM, BS, BZ, CY, EG, GB, GY, IE, IQ, IR, JM, JO, KW, LB, LY, NL, OM, PK, PR, QA, SA, SG, SR, SY, TT, YE);

 Trimeton (IT);

 Valemine (PH)

Mechanism of Action Competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract

Pharmacodynamics/Kinetics

Distribution: Vd: Children: 4-7 L/kg; Adults: 6-12 L/kg (Paton, 1985)

Protein binding: 33% (range: 29% to 37%) (Martínez-Gómez, 2007)

Metabolism: Hepatic via CYP450 enzymes (including CYP2D6 and other unidentified enzymes) to active and inactive metabolites; significant first-pass effect (Sharma, 2003)

Half-life elimination: Serum: Children: 10-13 hours; Adults: 14-24 hours (Paton, 1985)

Time to peak: 2-3 hours (Sharma, 2003)

Excretion: Urine (Sharma, 2003) Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. American Geriatrics Society 2012 Beers Criteria Update Expert Panel, "American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults," J Am Geriatr Soc, 2012, 60(4):616-31. [PubMed 22376048] 2. Martínez-Gómez MA, Villanueva-Camañas RM, Sagrado S, et al, "Evaluation of Enantioselective Binding of Antihistamines to Human Serum Albumin by ACE," Electrophoresis, 2007, 28(15):2635-43. [PubMed17605150] 3. Paton DM and Webster DR, "Clinical Pharmacokinetics of H1-Receptor Antagonists (The Antihistamines),"Clin Pharmacokinet, 1985, 10(6):477-97. [PubMed 2866055] 4. Sharma A and Hamelin BA, "Classic Histamine H1 Receptor Antagonists: A Critical Review of Their Metabolic and Pharmacokinetic Fate from a Bird's Eye View," Curr Drug Metab, 2003, 4(2):105-29.[PubMed 12678691]

Topic 8860 Version 52.0

Acetaminophen (paracetamol): Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Acetaminophen (paracetamol): Patient drug information" and see "Acetaminophen (paracetamol): Pediatric drug information" )

For abbreviations and symbols that may be used in Lexicomp (show table ) Special Alerts Acetaminophen: Transition of Pediatric Liquid Products to Standard Concentration June 2011

Based on recommendations provided by the Food and Drug Administration (FDA), all over-the- counter (OTC) pediatric single-ingredient acetaminophen liquid products will transition to a single concentration of 160 mg/5 mL; the transition has already begun and will continue into 2012. The concentration of acetaminophen infant drops (previously 80 mg/0.8 mL) will now be the same as children’s acetaminophen products (160 mg/5 mL) and as a result, new dosing on a volume-per-weight (or volume-per-age) basis will apply. The recommended mg/kg dose is unaffected and continues to be 10-15 mg/kg/dose. Healthcare professionals should be aware that during this transition, acetaminophen infant drop products with both the new and old concentrations may be available on pharmacy shelves. Parents may continue to use either product, but should verify concentration and use according to labeled dosing directions. Healthcare professionals should verify product concentration prior to providing dosing information.

Additional information can be found at http://www.tylenolprofessional.com/index.html

Brand Names: U.S.

 Acephen™ [OTC];

 APAP 500 [OTC];

 Aspirin Free Anacin® Extra Strength [OTC];  Cetafen® Extra [OTC];

 Cetafen® [OTC];

 Excedrin® Tension Headache [OTC];

 Feverall® [OTC];

 Infantaire [OTC];  Little Fevers™ [OTC];

 Mapap® Arthritis Pain [OTC];

 Mapap® Children's [OTC];

 Mapap® Extra Strength [OTC];  Mapap® Infant's [OTC];

 Mapap® Junior Rapid Tabs [OTC];

 Mapap® [OTC];

 Non-Aspirin Pain Reliever [OTC];  Nortemp Children's [OTC];

 Ofirmev™;

 Pain & Fever Children's [OTC];

 Pain Eze [OTC];

 Q-Pap Children's [OTC];  Q-Pap Extra Strength [OTC];

 Q-Pap Infant's [OTC];

 Q-Pap [OTC];

 RapiMed® Children's [OTC];

 RapiMed® Junior [OTC];

 Silapap Children's [OTC];

 Silapap Infant's [OTC];

 Triaminic™ Children's Fever Reducer Pain Reliever [OTC];

 Tylenol® 8 Hour [OTC];

 Tylenol® Arthritis Pain Extended Relief [OTC];

 Tylenol® Children's Meltaways [OTC];

 Tylenol® Children's [OTC];

 Tylenol® Extra Strength [OTC];

 Tylenol® Infant's Concentrated [OTC] [DSC];  Tylenol® Jr. Meltaways [OTC];

 Tylenol® [OTC];

 Valorin Extra [OTC];

 Valorin [OTC]

Brand Names: Canada

 Abenol®;

 Apo-Acetaminophen®;

 Atasol®;

 Novo-Gesic;

 Pediatrix;

 Tempra®;  Tylenol®

Pharmacologic Category

 Analgesic, Miscellaneous

Dosing: Adult

Note: No dose adjustment required if converting between different acetaminophen formulations. Limit acetaminophen dose from all sources (prescription and OTC) to <4 g daily.

Pain or fever:

Oral: Note: OTC dosing recommendations may vary by product and/or manufacturer.

Regular release: 325-650 mg every 4-6 hours or 1000 mg 3-4 times daily (maximum: 4 g daily)

Extended release: 1300 mg every 8 hours (maximum: 3.9 g daily)

Rectal: 325-650 mg every 4-6 hours or 1000 mg 3-4 times daily (maximum: 4 g daily)

I.V.:

<50 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 750 mg/dose; maximum daily dose: 75 mg/kg/day (≤3.75 g daily)

≥50 kg: 650 mg every 4 hours or 1000 mg every 6 hours; maximum single dose: 1000 mg/dose; maximum daily dose: 4 g daily

Dosing: Pediatric

(For additional information see "Acetaminophen (paracetamol): Pediatric drug information" )

Note: No dose adjustment required if converting between different acetaminophen formulations. Limit acetaminophen dose from all sources (prescription and OTC) to <4 g daily.

Pain or fever:

Oral: Note: OTC dosing recommendations may vary by product and/or manufacturer.

Infants and Children <12 years: 10-15 mg/kg/dose every 4-6 hours as needed; do not exceed 5 doses (2.6 g) in 24 hours; alternatively, the following age-based doses may be used; see table.

Children ≥12 years and Adolescents: Refer to adult dosing.

Acetaminophen Pediatric Dosing (Oral)1 Weight Dosage Weight (kg) Age (lbs) (mg)

1Manufacturer's recommendations; use of weight to select dose is preferred; if weight is not available, then use age. Manufacturer’s recommendations are based on weight in pounds (OTC labeling); weight in kg listed here is derived from pounds and rounded; kg weight listed also is adjusted to allow for continuous weight ranges in kg. OTC labeling instructs consumer to consult with physician for dosing instructions in children under 2 years of age.

2.7-5.3 6-11 0-3 mo 40

5.4-8.1 12-17 4-11 mo 80

8.2-10.8 18-23 1-2 y 120

10.9-16.3 24-35 2-3 y 160

16.4-21.7 36-47 4-5 y 240

21.8-27.2 48-59 6-8 y 320

27.3-32.6 60-71 9-10 y 400

32.7-43.2 72-95 11 y 480

Rectal:

Infants and Children <12 years: 10-20 mg/kg/dose every 4-6 hours as needed; do not exceed 5 doses (2.6 g) in 24 hours. Note: Although the perioperative use of high-dose rectal acetaminophen (eg, 25-45 mg/kg/dose) has been investigated in several studies, its routine use remains controversial; optimal doses and dosing frequency to ensure efficacy and safety have not yet been established (Buck, 2001).

Children ≥12 years and Adolescents: Refer to adult dosing.

I.V.:

Children 2-12 years: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 15 mg/kg/dose; maximum daily dose: 75 mg/kg/day (≤3.75 g daily)

Adolescents: Refer to adult dosing.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment Oral (Aronoff, 2007):

Children:

Clcr <10 mL/minute: Administer every 8 hours.

Intermittent hemodialysis or peritoneal dialysis: Administer every 8 hours.

CRRT: No adjustments necessary.

Adults:

Clcr 10-50 mL/minute: Administer every 6 hours.

Clcr <10 mL/minute: Administer every 8 hours.

Intermittent hemodialysis or peritoneal dialysis: No adjustment necessary.

CRRT: Administer every 8 hours.

I.V.: Clcr ≤30 mL/minute: Use with caution; consider decreasing daily dose and extending dosing interval.

Dosing: Hepatic Impairment Oral: Use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g daily have been reported. Avoid chronic use in hepatic impairment.

I.V.:

Mild-to-moderate impairment: Use with caution in hepatic impairment or active liver disease; manufacturer’s labeling suggests a reduced total daily dosage may be warranted, although no specific dosage adjustments are provided.

Severe impairment: Use is contraindicated.

Dosage Forms: U.S.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Caplet, oral: 500 mg

Cetafen® Extra: 500 mg

Mapap® Extra Strength: 500 mg

Mapap® Extra Strength: 500 mg [scored]

Pain Eze: 650 mg

Tylenol®: 325 mg

Tylenol® Extra Strength: 500 mg

Caplet, extended release, oral:

Mapap® Arthritis Pain: 650 mg

Tylenol® 8 Hour: 650 mg

Tylenol® Arthritis Pain Extended Relief: 650 mg

Capsule, oral: Mapap® Extra Strength: 500 mg

Captab, oral: 500 mg

Elixir, oral:

Mapap® Children's: 160 mg/5 mL (118 mL, 480 mL) [ethanol free; contains benzoic acid, propylene glycol, sodium benzoate; cherry flavor]

Gelcap, oral: 500 mg

Mapap®: 500 mg

Gelcap, rapid release, oral: 500 mg

Tylenol® Extra Strength: 500 mg

Geltab, oral: 500 mg

Excedrin® Tension Headache: 500 mg [contains caffeine 65 mg/geltab]

Injection, solution [preservative free]:

Ofirmev™: 10 mg/mL (100 mL)

Liquid, oral: 160 mg/5 mL (120 mL, 473 mL); 500 mg/5 mL (240 mL)

APAP 500: 500 mg/5 mL (237 mL) [ethanol free, sugar free; cherry flavor]

Mapap® Extra Strength: 500 mg/5 mL (237 mL) [contains propylene glycol, sodium 9 mg/15 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL, 473 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Silapap Children's: 160 mg/5 mL (118 mL, 237 mL, 473 mL) [ethanol free, sugar free; contains propylene glycol, sodium benzoate; cherry flavor]

Tylenol® Extra Strength: 500 mg/15 mL (240 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Solution, oral: 160 mg/5 mL (5 mL, 10 mL, 20 mL)

Pain & Fever Children's: 160 mg/5 mL (118 mL, 473 mL) [ethanol free, sugar free; contains propylene glycol, sodium 1 mg/5 mL, sodium benzoate; cherry flavor]

Solution, oral [drops]: 80 mg/0.8 mL (15 mL [DSC])

Infantaire: 80 mg/0.8 mL (15 mL, 30 mL)

Little Fevers™: 80 mg/mL (30 mL) [dye free, ethanol free, gluten free; contains propylene glycol, sodium benzoate; berry flavor]

Mapap®: 80 mg/0.8 mL (15 mL) [fruit flavor]

Q-Pap Infant's: 80 mg/0.8 mL (15 mL) [ethanol free; contains propylene glycol; fruit flavor]

Silapap Infant's: 80 mg/0.8 mL (15 mL, 30 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor] Suppository, rectal: 120 mg (12s); 325 mg (12s); 650 mg (12s)

Acephen™: 120 mg (12s, 50s, 100s); 325 mg (6s, 12s, 50s, 100s); 650 mg (12s, 50s, 100s)

Feverall®: 80 mg (6s, 50s); 120 mg (6s, 50s); 325 mg (6s, 50s); 650 mg (50s)

Suspension, oral: 160 mg/5 mL (5 mL, 10.15 mL, 20.3 mL)

Mapap® Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Mapap® Infant's: 160 mg/5 mL (59 mL) [dye free, ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Nortemp Children's: 160 mg/5 mL (118 mL) [ethanol free; contains propylene glycol, sodium benzoate; cotton candy flavor]

Pain & Fever Children's: 160 mg/5 mL (60 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; bubblegum flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Q-Pap Children's: 160 mg/5 mL (118 mL) [ethanol free; contains sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Tylenol® Children's: 160 mg/5 mL (120 mL) [dye free, ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Tylenol® Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; bubblegum flavor]

Tylenol® Children's: 160 mg/5 mL (60 mL, 120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; cherry flavor]

Tylenol® Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; grape flavor]

Tylenol® Children's: 160 mg/5 mL (120 mL) [ethanol free; contains propylene glycol, sodium 2 mg/5 mL, sodium benzoate; strawberry flavor]

Suspension, oral [drops]:

Mapap® Infant's: 80 mg/0.8 mL (15 mL, 30 mL) [ethanol free; contains propylene glycol, sodium benzoate; cherry flavor]

Tylenol® Infant's Concentrated: 80 mg/0.8 mL (30 mL [DSC]) [dye free; contains propylene glycol; cherry flavor]

Tylenol® Infant's Concentrated: 80 mg/0.8 mL (15 mL [DSC], 30 mL [DSC]) [ethanol free; contains sodium benzoate; cherry flavor]

Tylenol® Infant's Concentrated: 80 mg/0.8 mL (15 mL [DSC], 30 mL [DSC]) [ethanol free; contains sodium benzoate; grape flavor]

Syrup, oral: Triaminic™ Children's Fever Reducer Pain Reliever: 160 mg/5 mL (118 mL) [contains benzoic acid, sodium 6 mg/5 mL; bubblegum flavor]

Triaminic™ Children's Fever Reducer Pain Reliever: 160 mg/5 mL (118 mL) [contains sodium 5 mg/5 mL, sodium benzoate; grape flavor]

Tablet, oral: 325 mg, 500 mg

Aspirin Free Anacin® Extra Strength: 500 mg

Cetafen®: 325 mg

Mapap®: 325 mg

Non-Aspirin Pain Reliever: 325 mg

Q-Pap: 325 mg [scored]

Q-Pap Extra Strength: 500 mg [scored]

Tylenol®: 325 mg

Tylenol® Extra Strength: 500 mg

Valorin: 325 mg [sugar free]

Valorin Extra: 500 mg [sugar free]

Tablet, chewable, oral: 80 mg

Mapap® Children's: 80 mg [fruit flavor]

Tablet, orally disintegrating, oral: 80 mg, 160 mg

Mapap® Children's: 80 mg [bubblegum flavor]

Mapap® Children's: 80 mg [grape flavor]

Mapap® Junior Rapid Tabs: 160 mg [bubblegum flavor]

RapiMed® Children's: 80 mg [gluten free, sugar free; bubblegum flavor]

RapiMed® Children's: 80 mg [gluten free, sugar free; wild grape flavor]

RapiMed® Junior: 160 mg [gluten free, sugar free; bubblegum flavor]

RapiMed® Junior: 160 mg [gluten free, sugar free; wild grape flavor]

Tylenol® Children's Meltaways: 80 mg [scored; bubblegum flavor]

Tylenol® Children's Meltaways: 80 mg [scored; grape flavor]

Tylenol® Jr. Meltaways: 160 mg [bubblegum flavor]

Tylenol® Jr. Meltaways: 160 mg [grape flavor]

Generic Equivalent Available: U.S.

Yes: Excludes extended release products; injectable formulation

Administration

Suspension, oral: Shake well before pouring a dose.

Injection: For I.V. infusion only. May administer undiluted over 15 minutes. Compatibility

Stable in D5LR, D5NS, D5W, D10W, LR, NS

Y-site administration: Compatible: Buprenorphine, butorphanol, cimetidine, dexamethasone sodium phosphate, diphenhydramine, dolasetron, droperidol, fentanyl, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, ketorolac, lidocaine, lorazepam, mannitol, meperidine, methylprednisolone sodium succinate, metoclopramide, midazolam, morphine, nalbuphine, ondansetron, potassium chloride, prochlorperazine, sufentanil.

Use

Treatment of mild-to-moderate pain and fever (analgesic/antipyretic)

I.V.: Additional indication: Management of moderate-to-severe pain when combined with opioid analgesia

Medication Safety Issues Sound-alike/look-alike issues:

Acephen® may be confused with AcipHex®

FeverALL® may be confused with Fiberall®

Triaminic™ Children's Fever Reducer Pain Reliever may be confused with Triaminic® cough and cold products

Tylenol® may be confused with atenolol, timolol, Tylenol® PM, Tylox® Other safety concerns:

Duplicate therapy issues: This product contains acetaminophen, which may be a component of combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

Infant concentration change: The new infant acetaminophen concentration (160 mg/5 mL) is available. All children’s liquid acetaminophen products will now be the same 160 mg/5 mL concentration. However, the former infant acetaminophen concentration (80 mg/0.8 mL) may still be available in some pharmacies until supplies run out. Check concentrations closely prior to administering or dispensing (November 2011).

Injection: Reports of 10-fold overdose errors using the parenteral product have occurred in the U.S. and Europe; calculation of doses in "mg" and subsequent administration of the dose in "mL" using the commercially available concentration of 10 mg/mL contributed to these errors. Expressing doses as mgand mL, as well as pharmacy preparation of doses, may decrease error potential (Dart, 2012; ISMP, 2012). International issues:

Depon [Greece] may be confused with Depen brand name for penicillamine [U.S.]; Depin brand name for nifedipine [India]; Dipen brand name for diltiazem [Greece]

Duorol [Spain] may be confused with Diuril brand name for chlorothiazide [U.S., Canada]

Paralen [Czech Republic] may be confused with Aralen brand name for chloroquine [U.S., Mexico]

Adverse Reactions Significant Oral, Rectal: Frequency not defined:

Dermatologic: Rash

Endocrine & metabolic: May increase chloride, uric acid, glucose; may decrease sodium, bicarbonate, calcium

Hematologic: Anemia, blood dyscrasias (neutropenia, pancytopenia, leukopenia)

Hepatic: Bilirubin increased, alkaline phosphatase increased

Renal: Ammonia increased, nephrotoxicity with chronic overdose, analgesic nephropathy

Miscellaneous: Hypersensitivity reactions (rare)

I.V.:

>10%: Gastrointestinal: Nausea (adults 34%; children ≥5%), vomiting (adults 15%; children ≥5%)

1% to 10%:

Cardiovascular: Edema (peripheral), hypervolemia, hypo/hypertension, tachycardia

Central nervous system: Headache (adults 10%; children ≥1%), insomnia (adults 7%; children ≥1%), agitation (children ≥5%), anxiety, fatigue

Dermatologic: Pruritus (children ≥5%), rash

Endocrine & metabolic: Hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia

Gastrointestinal: Constipation (children ≥5%), abdominal pain, diarrhea

Hematologic: Anemia

Hepatic: Transaminases increased

Local: Infusion site pain

Neuromuscular & skeletal: Muscle spasms, pain in extremity, trismus

Ocular: Periorbital edema

Renal: Oliguria (children ≥1%)

Respiratory: Atelectasis (children ≥5%), breath sounds abnormal, dyspnea, hypoxia, pleural effusion, pulmonary edema, stridor, wheezing

All formulations: <1% (Limited to important or life-threatening): Anaphylaxis (rare), hypersensitivity reactions

Contraindications

Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or severe active liver disease (Ofirmev™)

Warnings/Precautions

Concerns related to adverse effects: • Hepatotoxicity: May cause severe hepatotoxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Use with caution in patients with chronic malnutrition.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.

Disease-related concerns:

• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency; rare reports of hemolysis have occurred.

• Hepatic impairment: Use with caution in patients with hepatic impairment or active liver disease; use of the intravenous formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease.

• Hypovolemia: Use the intravenous formulation with caution in patients with severe hypovolemia (eg, due to dehydration or blood loss).

• Renal impairment: Use with caution in patients with severe renal impairment; consider dosing adjustments.

Other warnings/precautions:

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.

• Self-medication (OTC use): When used for self-medication, patients should be instructed to contact healthcare provider if used for fever lasting >3 days or for pain lasting >10 days in adults or >5 days in children. OTC labeling limits the maximum daily dose to ≤3250 mg (dosage form specific).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Risk C: Monitor therapy

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Limit the maximum adult dose of lomitapide to 30 mg daily when used in combination with any weak CYP3A4 inhibitor. Risk D: Consider therapy modification

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Risk C: Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

Food: Rate of absorption may be decreased when given with food.

Herb/Nutraceutical: St John's wort may decrease acetaminophen levels.

Pregnancy Risk Factor

C (intravenous) (show table)

Pregnancy Implications

Animal reproduction studies have not been conducted with intravenous acetaminophen, therefore, acetaminophen I.V. is classified as pregnancy category C. Acetaminophen crosses the placenta and can be detected in cord blood, newborn serum, and urine immediately after delivery. An increased risk of teratogenic effects has not been observed following maternal use of acetaminophen during pregnancy. Prenatal constriction of the ductus arteriosus has been noted in case reports following maternal use during the third trimester. The use of acetaminophen in normal doses during pregnancy is not associated with an increased risk of miscarriage or still birth; however, an increase in fetal death or spontaneous abortion may be seen following maternal overdose if treatment is delayed. Frequent maternal use of acetaminophen during pregnancy may be associated with wheezing and asthma in early childhood. The absorption may be delayed and the bioavailability of acetaminophen may be decreased in some women during pregnancy due to delayed gastric emptying.

Lactation

Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)

Breast-Feeding Considerations

Low concentrations of acetaminophen are excreted into breast milk and can be detected in the urine of nursing infants. Adverse reactions have generally not been observed; however, a rash caused by acetaminophen exposure was reported in one breast-feeding infant.

Dietary Considerations

Some products may contain phenylalanine and/or sodium.

Pricing: U.S. (Medi-Span®)

Chewable (Acetaminophen Oral)

80 mg (30): $2.63

Chewable (Tylenol Go Tabs Extra Strength Oral)

500 mg (12): $3.32 Gel (ElixSure Fever/Pain Oral)

160 mg/5 mL (120 mL): $4.86

Liquid (Tylenol Extra Strength Oral)

1000 mg/30 mL (240 mL): $5.22

Liquid (Tylenol Oral)

500 mg/15 mL (240 mL): $5.23

Pack (Stanback Aspirin Free Oral)

950 mg (2): $0.32

Solution (Acetaminophen Oral)

160 mg/5 mL (10.15 mL): $0.56

Solution (Little Fevers Fever-Pain Rel Oral)

80 mg/mL (30 mL): $4.90

160 mg/5 mL (118 mL): $5.70

Solution (Ofirmev Intravenous)

10 mg/mL (100 mL): $14.92

Suppository (Acephen Rectal)

120 mg (50): $30.30

325 mg (50): $32.75

650 mg (12): $8.48

Suppository (Feverall Rectal)

80 mg (6): $4.81

120 mg (6): $4.81

325 mg (6): $4.81

650 mg (50): $33.08

Suspension (Nortemp Oral)

160 mg/5 mL (118 mL): $5.88

Suspension (Tylenol Childrens Oral)

160 mg/5 mL (120 mL): $5.69

Suspension (Tylenol Childrens/Flav Creator Oral)

160 mg/5 mL (120 mL): $8.10

Suspension (Tylenol Infants Oral)

80 mg/0.8 mL (30 mL): $8.00

Syrup (Triaminic Fever Reducer Oral) 160 mg/5 mL (118 mL): $4.85

Tablet, controlled release (Tylenol 8 Hour Oral)

650 mg (100): $10.94

Tablet, controlled release (Tylenol Arthritis Pain Oral)

650 mg (24): $3.66

Tablet, orally-disintegrating (Mapap Childrens Oral)

80 mg (30): $2.95

Tablet, orally-disintegrating (Tylenol Childrens Meltaways Oral)

80 mg (30): $3.61

Tablet, orally-disintegrating (Tylenol Jr Meltaways Oral)

160 mg (24): $4.85

Tablets (Acetaminophen Oral)

325 mg (100): $4.20

500 mg (100): $3.04

Tablets (Excedrin Tension Headache Oral)

500-65 mg (50): $5.75

Tablets (Mapap Extra Strength Oral)

500 mg (50): $3.29

Tablets (Pharbetol Extra Strength Oral)

500 mg (100): $2.97

Tablets (Pharbetol Oral)

325 mg (100): $2.25

Tablets (Tylenol Extra Strength Oral)

500 mg (100): $9.96

Tablets (Tylenol Oral)

325 mg (100): $7.54

Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

Monitoring Parameters

Serum APAP levels: Where acute overdose suspected and with long-term use in patients with hepatic disease; relief of pain or fever

International Brand Names  A-Mol (TH);

 Acamol (CN, IL);

 Acamol To-Go (IL);

 Acamoli Baby (IL);  Acamoli Forte suppositories for Kids (IL);

 ACET suppositories (SG);

 Acetalgin (CH);

 Acetamol (IT);

 Adinol (MX);  Adorem (CO);

 Afebrin (HK);

 Afebryl (LU);

 Alcocin (IN);

 Alginox (EC);

 Alvedon (SE);

 Ametrex (CO);

 Amol (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Analgiser (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Analphen (MX);

 Angela (TH);

 Aptamol (IN);

 Arfen (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, MY, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Atamel (PE);

 Avadol (MY);

 Ben-U-Ron (CH, PT);

 ben-u-ron (HU);

 Benuron (JP);

 Biogesic (PH, SG);

 Biogesic Suspension (HK);

 Biopain (PH);  Calapol (ID);

 Calpol (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IE, IQ, IR, JO, JP, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, PR, QA, SA, SC, SD, SL, SN, SY, TH, TN, TZ, UG, YE, ZM, ZW);  Causalon (AR);

 Cemol (TH);

 Cetta (TH);

 Children's Bufferin (CL);

 Children's S Tylenol (KP);

 Christamol (HK);  Claradol (MA);

 Cotemp (TH);

 Croix Blanche (LU);

 Curpol (LU);

 Dafalgan (BE, LU);

 Dafalgan odis (LU);

 Daga (TH);  Denamol (TH);

 Dirox (AR);

 Dismifen (MX);

 Dol-Stop (LU);

 Dolan Infantil (GT, HN, NI, SV);

 Dolex (UY);

 Dolgesic (ES);

 Doliprane (FR, IN, MA);

 Dolitabs (FR);

 Dolomol (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Dolorol (ZA);

 Dolprone (LU);

 Doluvital (MX);

 Dolviran (MX);

 Dymadon (AU);

 Efferalgan (HU, LU);  Efferalgan 500 (CR, DO, EE, GT, HN, NI, PA, SV);

 Efferalganodis (FR);

 Enelfa (LU);

 Europain (HK);

 Febridol (AU);

 Febrile Free (PH);

 Fervex (BR);

 Filanc (MX);

 Fortolin (HK);

 Gelocatil (ES);

 Geluprane 500 (FR);

 Hedex (IE);  Hoemal (MY, SG);

 Lekadol (HR);

 Lemgrip (BE, LU);

 Lonarid mono (LU);

 Lotemp (TH);

 Lupocet (HR);

 Mafidol (PE);

 Mejoralito Junior (MX);

 Mejoralito Pediátrico (MX);

 Metagesic (PH);

 Mexalen (AT, CZ, HU);

 Minopan (KP);  Momentum (LU);

 Mypara (TH);

 Nalgesik (ID);

 Napafen (EC);

 Napamol (ZA);

 Napran (PH);

 Naprex (ID);

 NEBS (JP);  Neuridon (LU);

 Nordinet Infantil (MX);

 Pacimol (IN);

 Pamol (DK, NZ);

 Panadol (AE, AU, BE, BF, BG, BH, BJ, CH, CI, CN, CY, CZ, EE, EG, ET, FI, FR, GB, GH, GM, GN, GR, HK, HU, ID, IE, IL, IQ, IR, IT, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, NL, NZ, OM, PE, PK, PL, PT, QA, RU, SA, SC, SD, SG, SL, SN, SY, TH, TN, TW, TZ, UG, YE, ZM, ZW);

 Panadol Actifast (MY, SG);

 Panadol Extend (SG);

 Panadol for Children (SG);  Panadon (HR);

 Panamax (AU);

 Panodil (DK, NO, SE);

 Para-IV (PH);

 Paracet (NO);

 Paracetamol (HR);  Paracetamol Pharmavit (HU);

 Paracetamol-ratiopharm (LU);

 Parageniol (PY);

 Paragin (TH);

 Paralgin (AU);  Paramol (IL, TW);

 Paramol Kat Drops (IL);

 Parapaed (DE);

 Parapaed Junior (NZ);

 Parapaed Six Plus (NZ);  Parcemol (HK);

 Parcemol Forte (HK);

 Parvid (PH);

 Paximol (SG);

 Pe-Tam (LU);

 Pedipan (KP);

 Penral-Night (KP);  Perdolan Mono (LU);

 Perfalgan (AT, AU, BG, CH, CZ, DE, DK, EE, FI, FR, GB, GR, IE, IN, IT, MT, NL, NO, NZ, PL, PT, RU, SE, SK, TR, ZA);

 Perfusalgan (BE);

 Pharmacen-M (MX);

 Pinex (NO);

 Plicet (HR);

 Poro (MY, PH, SG, TH);

 Raperon (KP);

 Rapidol (CN);

 Reliv (SE);

 Remedol (PR);

 Revanin (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Rhinapen elixir (KP);

 Rubophen (HU);  Salzone (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Sanmol Infusion (ID);

 Saridon (CO);

 Sedalito (MX);

 Selegesic (PH);

 Sensamol (IL);

 Setopain (KP);  Setopain ER (KP);

 Sinedol (DO, MX);

 Supadol mono (LU);

 Suspen ER (KP);

 Tafirol (PE);

 Tamoliv (ID);

 Tasmen (KP);

 Tempol (MY);

 Tempra (EC, ID, JP, LU, MX);

 Tempte (TW);

 Teramol (PH);

 Teramol Forte (PH);

 Toniker (TW);  Turpan (ID);

 Tylenol (BR, CH, DE, JP, KP, MX, PH, PT, TH, VE);

 Tylenol 8-hour (TH);

 Tylenol Acetaminophen Extended Relief (CL);

 Tylenol ER (KP);

 Tylenol Extra Fuerte (PY);

 Tylenol Forte (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Tylex (BB, BM, BS, BZ, GY, JM, MX, SR, TT);

 Winadol (CO, VE);  Winasorb (CR, DO, GT, HN, NI, PA, SV);

 Xebramol (TH);

 XL-Dol Infantil (MX)

Mechanism of Action

Although not fully elucidated, believed to inhibit the synthesis of prostaglandins in the central nervous system and work peripherally to block pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center

Pharmacodynamics/Kinetics

Onset of action:

Oral: <1 hour

I.V.: Analgesia: 5-10 minutes; Antipyretic: Within 30 minutes

Peak effect: I.V.: Analgesic: 1 hour

Duration:

I.V., Oral: Analgesia: 4-6 hours

I.V.: Antipyretic: ≥6 hours

Absorption: Primarily absorbed in small intestine (rate of absorption dependent upon gastric emptying); minimal absorption from stomach; varies by dosage form

Distribution: ~1 L/kg at therapeutic doses

Protein binding: 10% to 25% at therapeutic concentrations; 8% to 43% at toxic concentrations Metabolism: At normal therapeutic dosages, primarily hepatic metabolism to sulfate and glucuronide conjugates, while a small amount is metabolized by CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated rapidly with glutathione and inactivated to nontoxic cysteine and mercapturic acid conjugates. At toxic doses (as little as 4 g daily) glutathione conjugation becomes insufficient to meet the metabolic demand causing an increase in NAPQI concentrations, which may cause hepatic cell necrosis. Oral administration is subject to first pass metabolism.

Half-life elimination: Prolonged following toxic doses

Neonates: 7 hours (range: 4-10 hours)

Infants: ~4 hours (range: 1-7 hours)

Children: 3 hours (range: 2-5 hours)

Adolescents: ~3 hours (range: 2-4 hours)

Adults: ~2 hours (range: 2-3 hours); may be slightly prolonged in severe renal insufficiency

(Clcr<30 mL/minute): 2-5.3 hours

Time to peak, serum: Oral: Immediate release: 10-60 minutes (may be delayed in acute overdoses); I.V.: 15 minutes

Excretion: Urine (<5% unchanged; 60% to 80% as glucuronide metabolites; 20% to 30% as sulphate metabolites; ~8% cysteine and mercapturic acid metabolites) Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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Barr J, Fraser GL, Puntillo K, et al, “Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit,” Crit Care Med, 2013, 41(1):263-306. [PubMed23269131] 8. Bartle WR and Blakely JA, “Potentiation of Warfarin Anticoagulation by Acetaminophen,” JAMA, 1991, 265(10):1260. [PubMed 1995971] 9. Birmingham PK, Tobin MJ, Fisher DM, et al, “Initial and Subsequent Dosing of Rectal Acetaminophen in Children: A 24-Hour Pharmacokinetic Study of New Dose Recommendations,” Anesthesiology, 2001, 94(3):385-9. [PubMed 11374595] 10. Boeijinga JJ, Boerstra EE, Ris P, et al, “Interaction Between Paracetamol and Coumarin Anticoagulants,”Lancet, 1982, 1(8270):506. [PubMed 6121161] 11. Brackett CC and Bloch JD, “Phenytoin as a Possible Cause of Acetaminophen Hepatotoxicity: Case Report and Review of the Literature,” Pharmacotherapy, 2000, 20(2):229- 33. [PubMed 10678302] 12. Bradley JD, Brandt KD, Katz BP, et al, “Comparison of an Antiinflammatory Dose of Ibuprofen, an Analgesic Dose of Ibuprofen, and Acetaminophen in the Treatment of Patients With Osteoarthritis of the Knee,” N Engl J Med, 1991, 325(2):87-91. [PubMed 2052056] 13. Buck ML, “Perioperative Use of High-Dose Rectal Acetaminophen,” Pediatr Pharmacol (New York), 2001, 7(9). Available at http://www.medscape.com/viewarticle/415082_2 14. Burkhart KK, Janco N, Kulig KW, et al, “Cimetidine as Adjunctive Treatment for Acetaminophen Overdose,”Hum Exp Toxicol, 1995, 14(3):299-304. [PubMed 7779462] 15. Clissold SP, “Paracetamol and Phenacetin,” Drugs, 1986, 32(Suppl 4):46- 59. [PubMed 3552585] 16. Dart RC and Rumack BH, “Intravenous Acetaminophen in the United States: Iatrogenic Dosing Errors,”Pediatrics, 2012, 129(2):349-53. [PubMed 22271694] 17. Dionne RA, Campbell RA, Cooper SA, et al, “Suppression of Postoperative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen, and Acetaminophen Plus Codeine,”J Clin Pharmacol, 1983, 23(1):37-43. [PubMed 6341415] 18. “Drugs for Pain,” Med Lett Drugs Ther, 2000, 42(1085):73-8. [PubMed 10951654] 19. Duggan ST and Scott LJ, “Intravenous Paracetamol (Acetaminophen),” Drugs, 2009, 69(1):101- 13.[PubMed 19192939] 20. Gadisseur AP, Van Der Meer FJ, and Rosendaal FR, “Sustained Intake of Paracetamol (Acetaminophen) During Oral Anticoagulant Therapy With Coumarins Does Not Cause Clinically Important INR Changes: A Randomized Double-Blind Clinical Trial,” J Thromb Haemost, 2003, 1(4):714-7. [PubMed 12871405] 21. Gebauer MG, Nyfort-Hansen K, Henschke PJ, et al, “Warfarin and Acetaminophen Interaction,”Pharmacotherapy, 2003, 23(1):109-12. [PubMed 12523469] 22. Harrison PM, Keays R, Bray GP, et al, “Improved Outcome of Paracetamol-Induced Fulminant Hepatic Failure by Late Administration of Acetylcysteine,” Lancet, 1990, 335(8705):1572- 3. [PubMed 1972496] 23. Hochberg MC, Altman RD, April KT, et al, “American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee,”Arthritis Care Res (Hoboken), 2012, 64(4):465- 74. [PubMed 22563589] 24. Hylek EM, Heiman H, Skates SJ, et al, “Acetaminophen and Other Risk Factors for Excessive Warfarin Anticoagulation,” JAMA, 1998, 279(9):657-62. [PubMed 9496982] 25. Institute for Safe Medication Practices (ISMP), “IV Acetaminophen and Overdoses in Kids,” ISMP Medication Safety Alert, April 19, 2012. Available at http://ismp.org/Newsletters/acutecare/issue.asp?dt=20120419 26. Katzir Z, Baruch O, Hochman B, et al, “Spontaneous Remission of Paracetamol Induced Acute Renal Failure,” Clin Nephrol, 1995, 43(5):346. [PubMed 7634553] 27. Knoop KJ, Snook CP, Stephan M, et al, “Failure of N-Acetylcysteine (NAC) to Prevent Acetaminophen-Induced Renal Failure,” Vet Hum Toxicol, 1993, 35:336. 28. Kwan D, Bartle WR, and Walker SE, “The Effects of Acute and Chronic Acetaminophen Dosing on the Pharmacodynamics and Pharmacokinetics of (R)- and (S)-Warfarin,” Clin Pharmacol Ther, 1995, 57:212. 29. Lee WM, “Drug-Induced Hepatotoxicity,” N Engl J Med, 1995, 333(17):1118- 27. [PubMed 7565951] 30. Licht H, Seeff LB, and Zimmerman HJ, “Apparent Potentiation of Acetaminophen Hepatotoxicity by Alcohol,” Ann Intern Med, 1980, 92(4):511. 31. Mayoral CE, Marino RV, Rosenfeld W, et al, “Alternating Antipyretics: Is This an Alternative?” Pediatrics, 2000, 105(5):1009-12. [PubMed 10790455] 32. McClain CJ, Kromhout JP, Peterson FJ, et al, “Potentiation of Acetaminophen Hepatotoxicity by Alcohol,”JAMA, 1980, 244(3):251-3. [PubMed 7382090] 33. “Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain,” 6th ed, Glenview, IL: American Pain Society, 2008. 34. Rathmell JP, Viscomi CM, and Ashburn MA, “Management of Nonobstetric Pain During Pregnancy and Lactation,” Anesth Analg, 1997, 85(5):1074-87. [PubMed 9356103] 35. Rose SR, “Subtleties of Managing Acetaminophen Poisoning,” Am J Hosp Pharm, 1994, 51(24):3065-8.[PubMed 7856628] 36. Rubin RN, Mentzer RL, and Budzynski AZ, “Potentiation of Anticoagulant Effect of Warfarin by Acetaminophen (Tylenol®),” Clin Res, 1984, 32:698a. 37. Singer AJ, Carracio TR, and Mofenson HC, “The Temporal Profile of Increased Transaminase Levels in Patients With Acetaminophen-Induced Liver Dysfunction,” Ann Emerg Med, 1995, 26(1):49-53. [PubMed7793720] 38. Smilkstein MJ, Knapp GL, Kulig KW, et al, “Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose. Analysis of the National Multicenter Study (1976 to 1985),” N Engl J Med, 1988, 319(24):1557-62. [PubMed 3059186] 39. Stork CM, Rees S, Howland MA, et al, “Pharmacokinetics of Extended Relief vs Regular Release Tylenol® in a Simulated Human Overdose,” J Toxicol Clin Toxicol, 1996, 34(2):157- 62. [PubMed 8618248] 40. van den Bemt PM, Geven LM, Kuitert NA, et al, “The Potential Interaction Between Oral Anticoagulants and Acetaminophen in Everyday Practice,” Pharm World Sci, 2002, 24(5):201- 4. [PubMed 12426965] 41. van der Steeg J, Akhtar J, Burkhart K, et al, “Initial Prothrombin Time as a Predictor of Acetaminophen-Induced Hepatotoxicity,” Clin Toxicol, 1995, 33(5):508-9. 42. Watkins PB, Kaplowitz N, Slattery JT, et al, “Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized Controlled Trial,” JAMA, 2006, 296(1):87-93. [PubMed16820551] 43. Whitcomb DC and Block GD, “Association of Acetaminophen Hepatotoxicity With Fasting and Ethanol Use,” JAMA, 1994, 272(23):1845-50. [PubMed 7990219] 44. Williams HJ, Ward JR, Egger MJ, et al, “Comparison of Naproxen and Acetaminophen in a Two- Year Study of Treatment of Osteoarthritis of the Knee,” Arthritis Rheum, 1993, 36(9):1196- 206. [PubMed 8216413] 45. Woo OF, Anderson IB, Kim SY, et al, “Shorter Duration of N-Acetylcysteine (NAC) for Acute Acetaminophen Poisoning,” Clin Toxicol, 1995, 33(5):508. 46. Yerman B, Tseng J, and Caravati EM, “Pediatric Acetaminophen Ingestion: A Prospective Study of Referral Criteria,” Clin Toxicol, 1995, 33(5):530. 47. Zenger F, Russmann S, Junker E, et al, “Decreased Glutathione in Patients With Anorexia Nervosa. Risk Factor for Toxic Liver Injury?” Eur J Clin Nutr, 2004, 58(2):238- 43. [PubMed 14749742] 48. Zimmerman HJ and Maddrey WC, “Acetaminophen (Paracetamol) Hepatotoxicity With Regular Intake of Alcohol: Analysis of Instances of Therapeutic Misadventure,” Hepatology, 1995, 22(3):767-3. [PubMed7657281]

Topic 9242 Version 53.0

Codeine: Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Codeine: Patient drug information" and see "Codeine: Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table ) Special Alerts FDA Warns of Codeine Use in Children After Tonsillectomy and/or Adenoidectomy February 2013

The FDA has issued a Drug Safety Communication after reviewing reports of children who developed serious adverse effects, including death, after receiving codeine in the usual dosage range for pain relief following tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. Three deaths occurred in children that had evidence of a genetic variation (“ultrarapid metabolizers”) which results in faster and more complete conversion of codeine to morphine, possibly leading to overdose or death. The estimated incidence of this genetic variation is ~1-7 per 100 people, but may be higher in some ethnic groups.

The product labeling for codeine is being updated with a contraindication and boxed warning regarding its use as an analgesic in children undergoing tonsillectomy and/or adenoidectomy. Healthcare professionals should not prescribe codeine to children for pain after these procedures. Alternative analgesics should be used in this setting. For management of other types of pain in children, codeine should only be used if the benefits are anticipated to outweigh the risks. Parents and caregivers who observe signs of overdose in a child (eg, unusual sleepiness, confusion, or difficult or noisy breathing) should stop codeine administration and seek medical attention immediately.

Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Brand Names: Canada

 Codeine Contin®;

 PMS-Codeine;

 ratio-Codeine

Pharmacologic Category

 Analgesic, Opioid;

 Antitussive

Dosing: Adult

Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.

Pain management (analgesic): Oral:

Immediate release (tablet, oral solution): Initial: 15-60 mg every 4 hours as needed; maximum total daily dose: 360 mg/day; patients with prior opioid exposure may require higher initial doses. Note: The American Pain Society recommends an initial dose of 30-60 mg for adults with moderate pain (American Pain Society, 2008).

Controlled release: Codeine Contin® (Canadian availability; not available in U.S.): Note: Titrate at intervals of ≥48 hours until adequate analgesia has been achieved. Daily doses >600 mg/day should not be used; patients requiring higher doses should be switched to an opioid approved for use in severe pain. In patients who receive both Codeine Contin® and an immediate release or combination codeine product for breakthrough pain, the rescue dose of immediate release codeine product should be ≤12.5% of the total daily Codeine Contin® dose. Opioid-naive patients: Initial: 50 mg every 12 hours

Conversion from immediate release codeine preparations: Immediate release codeine preparations contain ~75% codeine base. Therefore, patients who are switching from immediate release codeine preparations may be transferred to a ~25% lower total daily dose of Codeine Contin®, equally divided into 2 daily doses.

Conversion from a combination codeine product (eg, codeine with acetaminophen or aspirin): See table:

Number of 30 mg Codeine Initial Dose of Maintenance Dose of Codeine Combination Tablets Daily Codeine Contin® Contin®

≤6 50 mg every 12 h 100 mg every 12 h

7-9 100 mg every 12 h 150 mg every 12 h

10-12 150 mg every 12 h 200 mg every 12 h

200-300 every 12 h (maximum: >12 200 mg every 12 h 300 mg every 12 h)

Conversion from another opioid analgesic: Using the patient’s current opioid dose, calculate an equivalent daily dose of immediate release codeine. A ~25% lower dose of Codeine Contin® should then be initiated, equally divided into 2 daily doses.

Discontinuation of therapy: Note: Gradual dose reduction is recommended if clinically appropriate. Initially reduce the total daily dose by 50% and administer equally divided into 2 daily doses for 2 days followed by a 25% reduction every 2 days thereafter.

Treatment of cough (unlabeled use): Oral: Reported doses vary; range: 7.5-120 mg/day as a single dose or in divided doses (Bolser, 2006; Smith, 2010); Note: The American College of Chest Physicians does not recommend the routine use of codeine as an antitussive in patients with upper respiratory infections (Bolser, 2006).

Dosing: Pediatric

(For additional information see "Codeine: Pediatric drug information" )

Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.

Pain management (analgesic; unlabeled use): Oral: Immediate release (tablet, oral solution): Initial: 0.5-1 mg/kg/dose every 4 hours as needed; maximum: 60 mg/dose (American Pain Society, 2008)

Dosing: Geriatric Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer’s recommendations: Clearance may be reduced; active metabolites may accumulate. Initiate at lower doses or longer dosing intervals followed by careful titration.

Alternate recommendations: The following guidelines have been used by some clinicians (Aronoff, 2007):

Clcr 10-50 mL/minute: Administer 75% of dose

Clcr <10 mL/minute: Administer 50% of dose

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied); however, initial lower doses or longer dosing intervals followed by careful titration are recommended.

Dosage Forms: U.S.

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

Solution, Injection, as phosphate:

Generic: 15 mg/mL (2 mL); 30 mg/mL (2 mL)

Solution, Oral, as phosphate:

Generic: 30 mg/5 mL (500 mL)

Tablet, Oral, as sulfate:

Generic: 15 mg, 30 mg, 60 mg

Dosage Forms: Canada

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

Tablet, controlled release:

Codeine Contin®: 50 mg, 100 mg, 150 mg, 200 mg

Generic Equivalent Available: U.S.

Yes

Controlled Substance

C-II

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Oral solution: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM302557.pdf

Administration

May administer without regard to meals. Take with food or milk to decrease adverse GI effects. Controlled release tablets: Codeine Contin® (Canadian availability; not available in U.S.): Tablets should be swallowed whole; do not chew, dissolve, or crush. All strengths may be halved, except the 50 mg tablets; half tablets should also be swallowed intact.

Use

Management of mild-to-moderately-severe pain

Use - Unlabeled

Short-term relief of cough in select patients

Medication Safety Issues Sound-alike/look-alike issues:

Codeine may be confused with Cardene®, Cordran®, iodine, Lodine High alert medication:

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

Adverse Reactions Significant

Frequency not defined.

Cardiovascular: Bradycardia, cardiac arrest, circulatory depression, flushing, hyper- /hypotension, palpitation, shock, syncope, tachycardia

Central nervous system: Abnormal dreams, agitation, anxiety, apprehension, chills, coordination impaired, depression, disorientation, dizziness, drowsiness, dysphoria, euphoria, faintness, fatigue, hallucinations, headache, insomnia, intracranial pressure increased, lightheadedness, nervousness, sedation, shakiness, somnolence, vertigo

Dermatologic: Pruritus, rash, urticaria

Gastrointestinal: Abdominal cramps/pain, anorexia, biliary tract spasm, constipation, diarrhea, nausea, pancreatitis, taste disturbance, vomiting, xerostomia

Genitourinary: Urinary hesitancy/retention

Neuromuscular & skeletal: Paresthesia, rigidity, tremor, weakness

Ocular: Blurred vision, diplopia, miosis, nystagmus, visual disturbances

Respiratory: Bronchospasm, dyspnea, laryngospasm, respiratory arrest, respiratory depression

Miscellaneous: Allergic reaction, diaphoresis

Contraindications

Hypersensitivity to codeine or any component of the formulation; respiratory depression in the absence of resuscitative equipment; acute or severe bronchial asthma or hypercarbia; presence or suspicion of paralytic ileus; postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to other opioid analgesics; cor pulmonale; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; suspected surgical abdomen; use with or within 14 days of MAO inhibitors.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Constipation: Use may cause or aggravate constipation; chronic use may result in obstructive bowel disease, particularly in those with underlying intestinal motility disorders.

• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics).

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression: May cause dose-related respiratory depression. The risk is increased in elderly patients, debilitated patients, and patients with conditions associated with hypoxia, hypercapnia, or upper airway obstruction.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease.

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; acute pancreatitis may cause constriction of sphincter of Oddi; may increase amylase/lipase levels.

• CNS depression/coma: Use with caution in patients with CNS depression or coma.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Gastrointestinal obstruction: Avoid use in patients with gastrointestinal obstruction, particularly paralytic ileus; chronic use may result in obstructive bowel disease.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. May also interfere with pupillary response and consciousness, thereby, affecting neurologic examination.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture. • Renal impairment: Use with caution in patients with severe renal impairment.

• Respiratory disease: Use with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

• Seizure disorders: May induce or aggravate seizures; use with caution in patients with seizure disorders.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• CYP2D6 “ultrarapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. The occurrence of this phenotype is seen in 0.5% to 1% of Chinese and Japanese, 0.5% to 1% of Hispanics, 1% to 10% of Caucasians, 3% of African-Americans, and 16% to 28% of North Africans, Ethiopians, and Arabs.

• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Consider decreasing the initial dose.

• Pediatric: [U.S. Boxed Warning]: Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and were found to have evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Deaths have also occurred in nursing infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers. Use is contraindicated in the postoperative pain management of children who have undergone tonsillectomy and/or adenoidectomy.

Dosage form specific issues:

• Sulfites: Some preparations contain sulfites which may cause allergic reactions.

Other warnings/precautions:

• Abuse/misuse/diversion: Healthcare provider should be alert to the potential for abuse, misuse, and diversion.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms.

Metabolism/Transport Effects

Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

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

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

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

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

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification

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

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Risk C: Monitor therapy Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Risk C: Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

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

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Risk C: Monitor therapy

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

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

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.

Herb/Nutraceutical: St John's wort may decrease codeine levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

Adverse events have been observed in animal reproduction studies. Opioid analgesics cross the placenta. In humans, birth defects (including some heart defects) have been associated with maternal use of opioid analgesics, including codeine, during the first trimester of pregnancy (Broussard, 2011). Use of opioids during pregnancy may produce physical dependence in the neonate. Symptoms of opioid withdrawal may include excessive crying, diarrhea, fever, hyper- reflexia, irritability, respiratory rate increased, sneezing, tremors, vomiting, or yawning; respiratory depression may occur in the newborn if opioids are used prior to delivery.

Lactation

Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)

Breast-Feeding Considerations

Codeine and its metabolite (morphine) are found in breast milk and can be detected in the serum of nursing infants. The relative dose to a nursing infant has been calculated to be ~1% of the weight-adjusted maternal dose. Higher levels of morphine may be found in the breast milk of lactating mothers who are “ultrarapid metabolizers” of codeine; patients with two or more copies of the variant CYP2D6*2 allele may have extensive conversion to morphine and thus increased opioid-mediated effects. In one case, excessively high serum concentrations of morphine were reported in a breast-fed infant following maternal use of acetaminophen with codeine. The mother was later found to be an “ultrarapid metabolizer” of codeine; symptoms in the infant included feeding difficulty and lethargy, followed by death. Caution should be used since most persons are not aware if they have the genotype resulting in “ultra-rapid metabolizer” status. When codeine is used in breast-feeding women, it is recommended to use the lowest dose for the shortest duration of time and observe the infant for increased sleepiness, difficulty in feeding or breathing, or limpness (FDA, 2007; Koren, 2006).

Pricing: U.S. (Medi-Span®)

Solution (Codeine Phosphate Injection)

15 mg/mL (2 mL): $2.87

30 mg/mL (2 mL): $3.05

Solution (Codeine Sulfate Oral)

30 mg/5 mL (500 mL): $128.44

Tablets (Codeine Sulfate Oral)

15 mg (100): $52.48

30 mg (100): $56.50

60 mg (100): $103.48 Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure, heart rate

Reference Range

Therapeutic: Not established

International Brand Names

 Actacode (AU);

 Antitussivum Burger (DE);

 Bronchicum (DE);

 Bronchodine (BE);

 Cobitussin (TW);

 Codant (IE);

 Codedrill sans sucre (FR);

 Codein (AR, KP);

 Codeine Linctus (GB);

 Codeine Phosphate (CY, CZ, NZ);

 Codeini phosphatis (HR);

 Codeinsaft von ct (DE);

 Codeintropfen Ribbeck (DE);  Codeintropfen von ct (DE);

 Codeinum Phosphorcum (PL);

 Codeinum phosphoricum Berlin-Chemie (DE);  Codeinum phosphoricum Compretten (DE);

 Codeisan (PT);

 Codenfan (FR);

 Coderit (MX);

 Coderpina (GT, HN, SV);

 codi OPT (DE);

 Codicaps (DE);

 Codicompren (DE);

 Codiforton (DE);

 Codin Linctus (IN);

 Codipertussin (DE);  Codipront mono (DE, LU);

 Codipront N (PH);

 Compretten (DE);

 Contrapect (DE);

 Dicton (DE, LU);

 Galcodine (GB);

 Glottyl (LU);

 Histaverin (ES);

 Kaodene (GB);

 Kodein (NO);

 Kodein Recip (SE);

 Kodein ”Dak” (DK);

 Lertus CD (MX);

 Neo-Codion[Sirup] (DE);

 Optipect (DE);

 Para-Co (TH);

 Pectinfant (LU);

 Pectoral Edulcor (LU);  Pulmocodeina (EC);

 Tricodein (DE);

 Tricodein Solco (AT, CH);

 Tryasol (DE);

 Tussamag-Codeinsaft (DE);  Tussipect Codein Tropfen Mono (DE);

 Tussoret (DE);

 Tussoretard (DE);

 Tylex CD (MX);

 Voltaren Forte (MX) Mechanism of Action

Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression

Pharmacodynamics/Kinetics

Onset of action: Oral: Immediate release: 0.5-1 hour

Peak effect: Oral: Immediate release: 1-1.5 hours

Duration: Immediate release: 4-6 hours

Distribution: ~3-6 L/kg

Protein binding: ~7% to 25%

Metabolism: Hepatic via UGT2B7 and UGT2B4 to codeine-6-glucuronide, via CYP2D6 to morphine (active), and via CYP3A4 to norcodeine. Morphine is further metabolized via glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide (active).

Bioavailability: 53%

Half-life elimination: ~3 hours

Time to peak, plasma: Immediate release: 1 hour; Controlled release (Canadian availability; not available in the U.S.): 3.3 hours

Excretion: Urine (~90%, ~10% of the total dose as unchanged drug); feces Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. American Academy of Pediatrics Committee on Drugs, “Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3): 776-89. [PubMed 11533352] 2. Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 18, 135. 3. Bolser DC, “Cough Suppressant and Pharmacologic Protussive Therapy: ACCP Evidence- Based Clinical Practice Guidelines,” Chest, 2006, 129(1 Suppl):238-48. [PubMed 16428717] 4. Broussard CS, Rasmussen SA, Reefhuis J, et al, "National Birth Defects Prevention Study: Maternal Treatment With Opioid Analgesics and Risk for Birth Defects," Am J Obstet Gynecol, 2011, 204(4):314.[PubMed 21345403] 5. Cardan E, “Fatal Case of Codeine Poisoning,” Lancet, 1981, 1(8233):1313. 6. de Groot AC and Conemans J, “Allergic Urticarial Rash From Oral Codeine,” Contact Dermatitis, 1986, 14(4):209-14. [PubMed 2941218] 7. Desjardins PJ, Cooper SA, Gallegos TL, et al, “The Relative Analgesic Efficacy of Propiram Fumarate, Codeine, Aspirin, and Placebo in Postimpaction Dental Pain,” J Clin Pharmacol, 1984, 24(1):35-42.[PubMed 6368614] 8. Ferrell BA, “Pain Management in Elderly People,” J Am Geriatr Soc, 1991, 39(1):64- 73. [PubMed 1670940] 9. Forbes JA, Keller CK, Smith JW, et al, “Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen-Codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery,” Pharmacotherapy, 1986, 6(5):211-8. [PubMed 3540871] 10. Irwin RS, Boulet LP, Cloutier MM, et al, “Managing Cough as a Defense Mechanism and as a Symptom: A Consensus Panel Report of the American College of Chest Physicians,” Chest, 198, 114(2):133-81.[PubMed 9725800] 11. Ivey HH and Kattwinkel J, “Danger of Actifed-C,” Pediatrics, 1976, 57(1):164- 5. [PubMed 1246497] 12. Jacobi J, Fraser GL, Coursin DB, et al, “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult,” Crit Care Med, 2002, 30(1):119-41. Available at http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003. [PubMed 11902253] 13. Kaiko RF, Wallenstein SL, Rogers AG, et al, “Narcotics in the Elderly,” Med Clin North Am, 1982, 66(5):1079-89. [PubMed 7132470] 14. Khan K and Chang J, “Neonatal Abstinence Syndrome Due to Codeine,” Arch Dis Child Fetal Neonatal Ed, 1997; 76(1): F59-60. [PubMed 9059191] 15. Koren G, Caims J, Chitayat D, et al, “Pharmacogenetics of Morphine Poisoning in a Breastfed Neonate of a Codeine-Prescribed Mother,” Lancet, 2006, 368(9536):704. [PubMed 16920476 ] 16. Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,”Chest, 2003, 123(3):897-922. [PubMed 12628894] 17. “Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain,” 6th ed, Glenview, IL: American Pain Society, 2008. 18. Reynolds EW, Riel-Romero RM, and Bada HS, “Neonatal Abstinence Syndrome and Cerebral Infarction Following Maternal Codeine Use During Pregnancy,” Clin Pediatr, 2007, 46(7):639- 45. [PubMed 17704497] 19. Smith SM, Schroeder K, and Fahey T, “Over-the-Counter (OTC) Medications for Acute Cough in Children and Adults in Ambulatory Settings (Review),” Cochrane Database Syst Rev, 2010, 9:1- 33. 20. Spigset O and Hagg S, “Analgesics and Breast-Feeding: Safety Considerations,” Paediatr Drugs, 2000, 2(3):223-38. [PubMed 10937472] 21. U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research, “Public Health Advisory: Use of Codeine by Some Breastfeeding Mothers May Lead to Life-Threatening Side Effects in Nursing Babies.” Available athttp://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvide rs/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm054717.htm 22. Wilkins D, Rollins DE, Seaman J, et al, “Quantitative Determination of Codeine and Its Major Metabolites in Human Hair by Gas Chromatography - Positive Ion Chemical Ionization Mass Spectrometry: A Clinical Application,” J Anal Toxicol, 1995, 19(5):269-74. [PubMed 7500611] 23. Zacher JL and Givone DM, “False-Positive Urine Opiate Screening Associated With Fluoroquinolone Use,”Ann Pharmacother, 2004, 38:1525-28. [PubMed 15252190]

Topic 9291 Version 50.0

Dexamethasone (systemic): Drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved.

(For additional information see "Dexamethasone (systemic): Patient drug information" and see "Dexamethasone (systemic): Pediatric drug information")

For abbreviations and symbols that may be used in Lexicomp (show table) Brand Names: U.S.

 Baycadron;

 Dexamethasone Intensol;

 DexPak 10 Day;

 DexPak 13 Day;

 DexPak 6 Day

Brand Names: Canada

 Apo-Dexamethasone®;

 Dexasone®;

 Dom-Dexamethasone;

 PHL-Dexamethasone;

 PMS-Dexamethasone;

 PRO-Dexamethasone;

 ratio-Dexamethasone

Pharmacologic Category

 Anti-inflammatory Agent;

 Antiemetic;

 Corticosteroid, Systemic

Dosing: Adult

Anti-inflammatory:

Oral, I.M., I.V.: 0.75-9 mg/day in divided doses every 6-12 hours

Intra-articular, intralesional, or soft tissue: 0.4-6 mg/day Extubation or airway edema: Oral, I.M., I.V.: 0.5-2 mg/kg/day in divided doses every 6 hours beginning 24 hours prior to extubation and continuing for 4-6 doses afterwards

Antiemetic:

Prophylaxis: Oral, I.V.: 10-20 mg 15-30 minutes before treatment on each treatment day

Continuous infusion regimen: Oral or I.V.: 10 mg every 12 hours on each treatment day

Mildly emetogenic therapy: Oral, I.M., I.V.: 4 mg every 4-6 hours

Delayed nausea/vomiting: Oral: 4-10 mg 1-2 times/day for 2-4 days or

8 mg every 12 hours for 2 days; then

4 mg every 12 hours for 2 days or

20 mg 1 hour before chemotherapy; then

10 mg 12 hours after chemotherapy; then

8 mg every 12 hours for 4 doses; then

4 mg every 12 hours for 4 doses

Multiple myeloma: Oral, I.V.: 40 mg/day, days 1 to 4, 9 to 12, and 17 to 20, repeated every 4 weeks (alone or as part of a regimen)

Cerebral edema: I.V. 10 mg stat, 4 mg I.M./I.V. (should be given as sodium phosphate) every 6 hours until response is maximized, then switch to oral regimen, then taper off if appropriate; dosage may be reduced after 2-4 days and gradually discontinued over 5-7 days

Dexamethasone suppression test (depression/suicide indicator) (unlabeled use): Oral: 1 mg at 11 PM, draw blood at 8 AM the following day for plasma cortisol determination

Cushing's syndrome, diagnostic: Oral: 1 mg at 11 PM, draw blood at 8 AM; greater accuracy for Cushing's syndrome may be achieved by the following:

Dexamethasone 0.5 mg by mouth every 6 hours for 48 hours (with 24-hour urine collection for 17-hydroxycorticosteroid excretion)

Differentiation of Cushing's syndrome due to ACTH excess from Cushing's due to other causes: Oral: Dexamethasone 2 mg every 6 hours for 48 hours (with 24-hour urine collection for 17-hydroxycorticosteroid excretion)

Multiple sclerosis (acute exacerbation): Oral: 30 mg/day for 1 week, followed by 4-12 mg/day for 1 month

Treatment of shock:

Addisonian crisis/shock (eg, adrenal insufficiency/responsive to steroid therapy): I.V.: 4-10 mg as a single dose, which may be repeated if necessary

Unresponsive shock (eg, unresponsive to steroid therapy): I.V.: 1-6 mg/kg as a single I.V. dose or up to 40 mg initially followed by repeat doses every 2-6 hours while shock persists

Physiological replacement: Oral, I.M., I.V. (should be given as sodium phosphate): 0.03-0.15 mg/kg/day or0.6-0.75 mg/m2/day in divided doses every 6-12 hours Acute mountain sickness (AMS)/high altitude cerebral edema (HACE) (unlabeled use):

Prevention: Oral: 2 mg every 6 hours or 4 mg every 12 hours starting on the day of ascent; may be discontinued after staying at the same elevation for 2-3 days or if descent is initiated; do not exceed a 10 day duration (Luks, 2010). Note: In situations of rapid ascent to altitudes >3500 meters (such as rescue or military operations), 4 mg every 6 hours may be considered (Luks, 2010).

Treatment: Oral, I.M., I.V.:

AMS: 4 mg every 6 hours (Luks, 2010)

HACE: Initial: 8 mg as a single dose; Maintenance: 4 mg every 6 hours until symptoms resolve (Luks, 2010)

Dosing: Pediatric

(For additional information see "Dexamethasone (systemic): Pediatric drug information")

Antiemetic (prior to chemotherapy): Refer to individual protocols and emetogenic potential: I.V.: 10 mg/m2/dose every 12-24 hours on days of chemotherapy for severely emetogenic chemotherapy courses

Anti-inflammatory and/or immunosuppressant: Oral, I.M., I.V.: 0.08-0.3 mg/kg/day or 2.5-10 mg/m2/day in divided doses every 6-12 hours

Extubation or airway edema: Oral, I.M., I.V.: 0.5-2 mg/kg/day in divided doses every 6 hours beginning 24 hours prior to extubation and continuing for 4-6 doses afterwards

Cerebral edema: I.V.: Loading dose: 1-2 mg/kg/dose as a single dose; maintenance: 1-1.5 mg/kg/day (maximum: 16 mg/day) in divided doses every 4-6 hours, taper off over 1-6 weeks

Croup (laryngotracheobronchitis): Oral, I.M., I.V.: 0.6 mg/kg once; usual maximum dose: 16 mg (doses as high as 20 mg have been used) (Bjornson, 2004; Hegenbarth, 2008; Rittichier, 2000); a single oral dose of 0.15 mg/kg has been shown effective in children with mild-to-moderate croup (Russell, 2004; Sparrow, 2006)

Bacterial meningitis: Infants and Children >6 weeks: I.V.: 0.15 mg/kg/dose every 6 hours for the first 2-4 days of antibiotic treatment; start dexamethasone 10-20 minutes before or with the first dose of antibiotic

Physiologic replacement: Oral, I.M., I.V.: 0.03-0.15 mg/kg/day or 0.6-0.75 mg/m2/day in divided doses every 6-12 hours

Acute mountain sickness (AMS)/high altitude cerebral edema (HACE) (unlabeled use): Oral, I.M., I.V.: 0.15 mg/kg/dose every 6 hours; consider using for high altitude pulmonary edema because of associated HACE with this condition (Luks, 2010; Pollard, 2001)

Dosing: Geriatric

Refer to adult dosing. Use cautiously in the elderly in the smallest possible dose.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling; use with caution. Hemodialysis or peritoneal dialysis: Supplemental dose is not necessary. Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosage Forms: U.S.

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

Concentrate, Oral:

Dexamethasone Intensol: 1 mg/mL (30 mL) [contains alcohol, usp; unflavored flavor]

Elixir, Oral:

Baycadron: 0.5 mg/5 mL (237 mL) [contains alcohol, usp, benzoic acid, fd&c red #40, propylene glycol; raspberry flavor]

Generic: 0.5 mg/5 mL (237 mL)

Solution, Oral:

Generic: 0.5 mg/5 mL (240 mL, 500 mL)

Solution, Injection, as sodium phosphate:

Generic: 4 mg/mL (1 mL, 5 mL, 30 mL); 10 mg/mL (1 mL, 10 mL)

Solution, Injection, as sodium phosphate [preservative free]:

Generic: 10 mg/mL (1 mL)

Tablet, Oral:

DexPak 10 Day: 1.5 mg [scored; contains fd&c red #40 aluminum lake]

DexPak 13 Day: 1.5 mg [scored; contains fd&c red #40 aluminum lake]

DexPak 6 Day: 1.5 mg [scored; contains fd&c red #40 aluminum lake]

Generic: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 6 mg

Generic Equivalent Available: U.S.

May be product dependent

Administration

Oral: Administer with meals to decrease GI upset.

I.V.: Administer as a 5-10 minute bolus; rapid injection is associated with a high incidence of perineal discomfort.

Compatibility

Stable in D5W, NS.

Y-site administration: Compatible: Acetaminophen, acyclovir, allopurinol, amifostine, amikacin, amphotericin B cholesteryl sulfate complex, amsacrine, anidulafungin, aztreonam, bivalirudin, caffeine citrate, cefepime, cisatracurium, cisplatin, cladribine, cyclophosphamide, cytarabine, dexmedetomidine, docetaxel, doripenem, doxorubicin, doxorubicin liposome, etoposide phosphate, famotidine, fentanyl, filgrastim, fluconazole, fludarabine, foscarnet, gallium nitrate, gemcitabine, granisetron, heparin, heparin with hydrocortisone sodium succinate, hetastarch in lactate electrolyte injection (Hextend®), levofloxacin, linezolid, lorazepam, melphalan, meperidine, meropenem, methadone, milrinone, ondansetron, oxaliplatin, paclitaxel, pemetrexed, piperacillin/tazobactam, potassium chloride, propofol, remifentanil, sargramostim, sodium bicarbonate, sufentanil, tacrolimus, telavancin, teniposide, theophylline, thiotepa, vinorelbine, vitamin B complex with C, zidovudine. Incompatible: Ciprofloxacin, diphenhydramine, fenoldopam, fosaprepitant, haloperidol, idarubicin, midazolam, pantoprazole, topotecan. Variable (consult detailed reference):Hydromorphone, methotrexate, metoclopramide, morphine.

Compatibility in syringe: Compatible: Caffeine citrate, dimenhydrinate, droperidol, furosemide, granisetron, ketamine, ketorolac, metoclopramide, palonosetron, ranitidine, sufentanil. Incompatible: Doxapram, famotidine, glycopyrrolate, pantoprazole, promethazine. Variable (consult detailed reference):Diphenhydramine, hydromorphone, midazolam, ondansetron.

Use

Primarily as an anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases including those of allergic, dermatologic, endocrine, hematologic, inflammatory, neoplastic, nervous system, renal, respiratory, rheumatic, and autoimmune origin; may be used in management of cerebral edema, chronic swelling, as a diagnostic agent, diagnosis of Cushing’s syndrome, antiemetic

Use - Unlabeled

Dexamethasone suppression test as an indicator of depression and/or risk of suicide; prevention and treatment of acute mountain sickness and high altitude cerebral edema; accelerate fetal lung maturation in patients with preterm labor

Medication Safety Issues Sound-alike/look-alike issues:

Dexamethasone may be confused with desoximetasone, dextroamphetamine

Decadron® may be confused with Percodan®

Adverse Reactions Significant

Frequency not defined.

Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, cardiomyopathy, CHF, circulatory collapse, edema, hypertension, myocardial rupture (post-MI), syncope, thromboembolism, vasculitis

Central nervous system: Depression, emotional instability, euphoria, headache, intracranial pressure increased, insomnia, malaise, mood swings, neuritis, personality changes, pseudotumor cerebri (usually following discontinuation), psychic disorders, seizure, vertigo

Dermatologic: Acne, allergic dermatitis, alopecia, angioedema, bruising, dry skin, erythema, fragile skin, hirsutism, hyper-/hypopigmentation, hypertrichosis, perianal pruritus (following I.V. injection), petechiae, rash, skin atrophy, skin test reaction impaired, striae, urticaria, wound healing impaired

Endocrine & metabolic: Adrenal suppression, carbohydrate tolerance decreased, Cushing's syndrome, diabetes mellitus, glucose intolerance decreased, growth suppression (children), hyperglycemia, hypokalemic alkalosis, menstrual irregularities, negative nitrogen balance, pituitary-adrenal axis suppression, protein catabolism, sodium retention Gastrointestinal: Abdominal distention, appetite increased, gastrointestinal hemorrhage, gastrointestinal perforation, nausea, pancreatitis, peptic ulcer, ulcerative esophagitis, weight gain

Genitourinary: Altered (increased or decreased) spermatogenesis

Hepatic: Hepatomegaly, transaminases increased

Local: Postinjection flare (intra-articular use), thrombophlebitis

Neuromuscular & skeletal: Arthropathy, aseptic necrosis (femoral and humoral heads), fractures, muscle mass loss, myopathy (particularly in conjunction with neuromuscular disease or neuromuscular-blocking agents), neuropathy, osteoporosis, parasthesia, tendon rupture, vertebral compression fractures, weakness

Ocular: Cataracts, exophthalmos, glaucoma, intraocular pressure increased

Renal: Glucosuria

Respiratory: Pulmonary edema

Miscellaneous: Abnormal fat deposition, anaphylactoid reaction, anaphylaxis, avascular necrosis, diaphoresis, hiccups, hypersensitivity, impaired wound healing, infections, Kaposi's sarcoma, moon face, secondary malignancy

Contraindications

Hypersensitivity to dexamethasone or any component of the formulation; systemic fungal infections, cerebral malaria

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: May cause hypercorticism or suppression of hypothalamic- pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids donot provide the systemic steroid needed to treat patients having trauma, surgery, or infections.

• Immunosuppression: Prolonged use of corticosteroids may also increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Exposure to chickenpox should be avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids should not be used for cerebral malaria or viral hepatitis. Close observation is required in patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only in conjunction with antituberculosis treatment).

• Kaposi's sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi's sarcoma (case reports); if noted, discontinuation of therapy should be considered. • Myopathy: Acute myopathy has been reported with high dose corticosteroids, usually in patients with neuromuscular transmission disorders; may involve ocular and/or respiratory muscles; monitor creatine kinase; recovery may be delayed.

• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including depression, euphoria, insomnia, mood swings, and personality changes. Pre-existing psychiatric conditions may be exacerbated by corticosteroid use.

Disease-related concerns:

• Adrenal insufficiency: Dexamethasone does not provide adequate mineralocorticoid activity in adrenal insufficiency (may be employed as a single dose while cortisol assays are performed). The lowest possible dose should be used during treatment; discontinuation and/or dose reductions should be gradual.

• Cardiovascular disease: Use with caution in patients with HF; long-term use has been associated with fluid retention and hypertension.

• Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose production/regulation leading to hyperglycemia.

• Gastrointestinal disease: Use with caution in patients with GI diseases (diverticulitis, peptic ulcer, ulcerative colitis) due to perforation risk.

• Head injury: Increased mortality was observed in patients receiving high-dose I.V. methylprednisolone. High-dose corticosteroids should not be used for the management of head injury.

• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms has occurred especially during initial treatment with corticosteroids.

• Myocardial infarction (MI): Use with caution following acute MI; corticosteroids have been associated with myocardial rupture.

• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use. Consider routine eye exams in chronic users.

• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long- term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.

• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.

• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.

Special populations: • Elderly: Because of the risk of adverse effects, systemic corticosteroids should be used cautiously in the elderly in the smallest possible effective dose for the shortest duration.

• Pediatrics: May affect growth velocity; growth should be routinely monitored in pediatric patients.

Other warnings/precautions:

• Discontinuation of therapy: Withdraw therapy with gradual tapering of dose.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P- glycoprotein;Induces CYP2A6 (weak/moderate), CYP2B6 (weak/moderate), CYP2C9 (weak/moderate), CYP3A4 (strong), P-glycoprotein

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program)

Acetylcholinesterase Inhibitors: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Risk X: Avoid combination

Aminoglutethimide: May increase the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy

Amphotericin B: Corticosteroids (Systemic) may enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapy

Antacids: May decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects. Risk D: Consider therapy modification

Antidiabetic Agents: Corticosteroids (Systemic) may diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Corticosteroids (Systemic).Risk C: Monitor therapy

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Risk X: Avoid combination

Aprepitant: May increase the serum concentration of Corticosteroids (Systemic). Risk D: Consider therapy modification

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor clinical response. Reduce the oral aripiprazole dose to 10-15 mg/day if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

Asparaginase (E. coli): May increase the serum concentration of Dexamethasone (Systemic). This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism.Risk C: Monitor therapy

Asparaginase (Erwinia): May increase the serum concentration of Dexamethasone (Systemic). This is thought to be due to an asparaginase-related decrease in hepatic proteins responsible for dexamethasone metabolism.Risk C: Monitor therapy

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Barbiturates: May decrease the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy

BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Corticosteroids (Oral). Risk C: Monitor therapy

Boceprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Boceprevir. Management: Avoid strong CYP3A4 inducers with boceprevir when possible, and closely monitor response to boceprevir if such a combination cannot be avoided. Carbamazepine, phenytoin, phenobarbital, rifampin, and St. John's wort are considered contraindicated. Risk D: Consider therapy modification

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Risk X: Avoid combination

Calcitriol: Corticosteroids (Systemic) may diminish the therapeutic effect of Calcitriol. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Corticosteroids (Systemic).Exceptions: Bepridil [Off Market]. Risk C: Monitor therapy

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modification

Cobicistat: Dexamethasone (Systemic) may decrease the serum concentration of Cobicistat. Risk C: Monitor therapy Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Risk C: Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

CycloSPORINE (Systemic): Dexamethasone (Systemic) may decrease the serum concentration of CycloSPORINE (Systemic). Dexamethasone (Systemic) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Dexamethasone (Systemic). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

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

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

CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with p-glycoprotein inducers when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering p-glycoprotein inducers, particularly strong inducers. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

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

Deferasirox: Corticosteroids (Systemic) may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Elvitegravir: Dexamethasone (Systemic) may decrease the serum concentration of Elvitegravir. Risk C: Monitor therapy

Enzalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Risk X: Avoid combination

Estrogen Derivatives: May increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Risk X: Avoid combination

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Risk D: Consider therapy modification

Fluconazole: May decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy

Fosaprepitant: May increase the serum concentration of Corticosteroids (Systemic). The active metabolite aprepitant is likely responsible for this effect. Risk D: Consider therapy modification

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse drug reactions, consider increasing gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers. Carefully monitor clinical response and development of adverse reactions. Risk D: Consider therapy modification

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose by 2-fold when adding a strong CYP3A4 inducer. Titrate the guanfacine dose up to a max of 8 mg/day when starting guanfacine in a patient who is taking a strong CYP3A4 inhibitor. Risk D: Consider therapy modification

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Management: Consider avoiding CYP3A4 inducing herbs in order to avoid therapeutic failure of the substrate. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Risk D: Consider therapy modification

Indacaterol: May enhance the hypokalemic effect of Corticosteroids (Systemic). Risk C: Monitor therapy

Isoniazid: Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid. Risk C: Monitor therapy

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Risk X: Avoid combination

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

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4- hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Lenalidomide: Dexamethasone (Systemic) may enhance the thrombogenic effect of Lenalidomide. Risk D: Consider therapy modification

Loop Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination

Macrolide Antibiotics: May decrease the metabolism of Corticosteroids (Systemic). Exceptions: Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with Clcr less than 30 mL/min. Risk D: Consider therapy modification

Mifepristone: May diminish the therapeutic effect of Corticosteroids (Systemic). Mifepristone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (e.g., for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Risk X: Avoid combination

Mitotane: May decrease the serum concentration of Corticosteroids (Systemic). Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Neuromuscular-Blocking Agents (Nondepolarizing): May enhance the adverse neuromuscular effect of Corticosteroids (Systemic). Increased muscle weakness, possibly progressing to polyneuropathies and myopathies, may occur. Risk D: Consider therapy modification

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Management: Consider alternatives to nifedipine for patients who are using strong CYP3A4 inducers. At least one specific brand of nifedipine (Adalat CC) lists this combination as contraindicated. Risk D: Consider therapy modification

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

NSAID (COX-2 Inhibitor): Corticosteroids (Systemic) may enhance the adverse/toxic effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy

NSAID (Nonselective): Corticosteroids (Systemic) may enhance the adverse/toxic effect of NSAID (Nonselective).Risk C: Monitor therapy

Pazopanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pazopanib. Risk X: Avoid combination

Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Avoid use of perampanel with strong CYP3A inducers other than enzyme- inducing antiepileptic drugs (EIAEDs). Increase perampanel starting dose to 4 mg/day when used with EIAEDs such as phenytoin, carbamazepine, or oxcarbazepine. Risk X: Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P- glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p- glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P- glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p- glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Pomalidomide: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Pomalidomide. Risk X: Avoid combination

Ponatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ponatinib. Risk X: Avoid combination

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Risk X: Avoid combination

Primidone: May decrease the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: Quetiapine dose increases to as much as 5 times the regular dose may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7-14 days of discontinuing the inducer. Risk D: Consider therapy modification

Quinolone Antibiotics: May enhance the adverse/toxic effect of Corticosteroids (Systemic). Risk of tendon-related side effects, including tendonitis and rupture, may be enhanced. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Risk X: Avoid combination

Rifamycin Derivatives: May increase the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy

Rilpivirine: Dexamethasone (Systemic) may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination

Salicylates: May enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification

Telaprevir: Corticosteroids (Systemic) may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Corticosteroids (Systemic). Management: Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives. If used together, employ extra caution and monitor closely for excessive corticosteroid effects and diminished telaprevir effects. Risk D: Consider therapy modification

Telaprevir: May increase the serum concentration of Corticosteroids. Corticosteroids may decrease the serum concentration of Telaprevir. Management: Concurrent use of telaprevir and systemic corticosteroids is not recommended. When possible, consider alternatives. If used together, employ extra caution and monitor closely for excessive corticosteroid effects and diminished telaprevir effects. Risk D: Consider therapy modification

Thalidomide: Dexamethasone (Systemic) may enhance the dermatologic adverse effect of Thalidomide. Dexamethasone (Systemic) may enhance the thrombogenic effect of Thalidomide. Risk D: Consider therapy modification

Thiazide Diuretics: Corticosteroids (Systemic) may enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or other non- disease modifying antirheumatic drugs (non-DMARDs) is permitted, and this warning seems to particularly focused on more potent immunosuppressants. Risk X: Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Risk X: Avoid combination

Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk C: Monitor therapy

Urea Cycle Disorder Agents: Corticosteroids (Systemic) may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Corticosteroids (Systemic) may increase protein catabolism and plasma ammonia concentrations, thereby increasing the doses of Urea Cycle Disorder Agents needed to maintain these concentrations in the target range. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Corticosteroids (Systemic) may enhance the adverse/toxic effect of Vaccines (Live). Risk D: Consider therapy modification

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Warfarin: Corticosteroids (Systemic) may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Food: Dexamethasone interferes with calcium absorption. Limit caffeine.

Herb/Nutraceutical: Avoid cat's claw, echinacea (have immunostimulant properties).

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

Adverse events have been observed with corticosteroids in animal reproduction studies. Dexamethasone crosses the placenta; and is partially metabolized to an inactive metabolite by placental enzymes. Due to its positive effect on stimulating fetal lung maturation, the injection is often used in patients with premature labor (24-34 weeks gestation). Some studies have shown an association between first trimester systemic corticosteroid use and oral clefts; adverse events in the fetus/neonate have been noted in case reports following large doses of systemic corticosteroids during pregnancy. Women exposed to dexamethasone during pregnancy for the treatment of an autoimmune disease may contact the OTIS Autoimmune Diseases Study at 877-311-8972.

Lactation Excretion in breast milk unknown/use caution

Breast-Feeding Considerations

Corticosteroids are excreted in human milk; information specific to dexamethasone has not been located.

Dietary Considerations

May be taken with meals to decrease GI upset. May need diet with increased potassium, pyridoxine, vitamin C, vitamin D, folate, calcium, and phosphorus.

Pricing: U.S. (Medi-Span®)

Concentrate (Dexamethasone Intensol Oral)

1 mg/mL (30 mL): $23.74

Elixir (Baycadron Oral)

0.5 mg/5 mL (237 mL): $79.10

Elixir (Dexamethasone Oral)

0.5 mg/5 mL (237 mL): $63.68

Solution (Dexamethasone Oral)

0.5 mg/5 mL (240 mL): $63.69

Solution (Dexamethasone Sod Phosphate PF Injection)

10 mg/mL (1 mL): $3.88

Solution (Dexamethasone Sodium Phosphate Injection)

4 mg/mL (5 mL): $2.34

10 mg/mL (10 mL): $4.80

Tablets (Dexamethasone Oral)

0.5 mg (100): $20.76

0.75 mg (100): $36.39

1 mg (100): $35.00

1.5 mg (100): $27.14

2 mg (100): $68.54

4 mg (100): $64.25

6 mg (100): $107.07

Tablets (DexPak 10 Day Oral)

1.5 mg (35): $44.94

Tablets (DexPak 13 Day Oral)

1.5 mg (51): $51.36

Tablets (DexPak 6 Day Oral) 1.5 mg (21): $31.20

Disclaimer: The pricing data provided represent a median AWP and/or AAWP price for the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for charging or reimbursement functions. Pricing data is updated monthly.

Monitoring Parameters

Hemoglobin, occult blood loss, serum potassium, glucose, growth in children

Reference Range

Dexamethasone suppression test, overnight: 8 AM cortisol <6 mcg/100 mL (dexamethasone 1 mg); plasma cortisol determination should be made on the day after giving dose

International Brand Names

 Aacidexam (BE);

 Alin (CR, DO, GT, NI, PA, SV);

 BiDexol (TH);

 Coenkasu (TW);

 Cordex (PH);

 Corodex (UY);

 Cortidex (ID);

 Cortidexason (DE);

 Cortyk (CN);

 Decadron (AR, BF, BJ, BR, CI, CO, DE, EC, ET, GH, GM, GN, GR, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, PK, PT, PY, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);

 Decadronal (BR);

 Decan (PH, SG);

 Decasone (ZA);

 Decdan (IN);

 Decilone (PH);

 Dectancyl (AE, BH, CY, EG, FR, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Demexam (EC);

 Desalark (IT);

 Dexacort (PE);

 Dexacort Forte (IL);

 Dexacortal (SE);

 Dexaflam (DE);

 Dexagel (TH);

 Dexalocal (CR, HN, NI, PA, SV);  Dexalone (MY);

 Dexamed (CZ, SG);

 Dexametason (FI);

 Dexamethasone (IL, NZ);

 Dexamin (VE);

 Dexano (TH);  Dexasolone (KP);

 Dexasone (HK, TH);

 Dexazone (TW);

 Dexmethsone (AU, NZ);

 Dexona (AE, BH, CY, EG, IN, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE);

 Fortecortin (AT, BG, CH, CZ, DE, NO, RU);

 Lodexa (TH);

 Oftan-Dexa (FI);

 Onadron (TR);

 Oradexon (AE, BF, BH, BJ, CI, CN, CY, EG, ET, FI, GH, GM, GN, GR, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, NL, OM, PE, PH, PT, QA, SA, SC, SD, SL, SN, SY, TN, TW, TZ, UG, YE, ZM, ZW);

 Penatone (MY);

 Roximeth (MY);

 Santeson (PH);

 Spersadex (NO);

 Supertendin (DE);  Thilodexine (GR);

 Vexamet (PH);

 Visumetazone (IT);

 Wymesone (IN)

Mechanism of Action

Decreases inflammation by suppression of neutrophil migration, decreased production of inflammatory mediators, and reversal of increased capillary permeability; suppresses normal immune response. Dexamethasone's mechanism of antiemetic activity is unknown.

Pharmacodynamics/Kinetics

Onset of action: Acetate: Prompt

Duration of metabolic effect: 72 hours; acetate is a long-acting repository preparation Metabolism: Hepatic

Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological half-life: 36-54 hours

Time to peak, serum: Oral: 1-2 hours; I.M.: ~8 hours

Excretion: Urine and feces Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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