Revisions

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ISOtretinoin – October 2017

The Pronunciation, Medication Safety Issues, Generic Availability (US), Pregnancy Risk Factor, Warnings: Additional Pediatric Considerations, Dosing: Usual, and Dosage Forms fields were omitted from the ISOtretinoin monograph in the Pediatric & Neonatal Dosage Handbook 24th edition during the pagination process.

Fields that were omitted from the print edition are highlighted below:

ISOtretinoin (eye soe TRET i noyn)

Medication Safety Issues

Sound-alike/look-alike issues:

Accutane may be confused with Accolate, Accupril

Claravis may be confused with Cleviprex

ISOtretinoin may be confused with tretinoin

Other safety concerns:

Isotretinoin may be confused with tretinoin (which is also called all-trans retinoic acid, or ATRA); while both products may have uses in cancer treatment, they are not interchangeable.

Related Information

  • Oral Medications That Should Not Be Crushed or Altered
  • Safe Handling of Hazardous Drugs

Brand Names: US

  • Absorica
  • Amnesteem
  • Claravis
  • Myorisan
  • Zenatane

Brand Names: Canada

  • Accutane
  • Clarus
  • Epuris

Index Terms

  • 13-cis-Retinoic Acid
  • 13-cis-Vitamin A Acid
  • 13-CRA
  • Cis-Retinoic Acid
  • Accutane
  • Isotretinoinum

Therapeutic Category

  • Acne Products
  • Antineoplastic Agent, Retinoic Acid Derivatives
  • Retinoic Acid Derivative
  • Vitamin A Derivative

Generic Availability (US)

No

Use

Treatment of severe recalcitrant nodular acne unresponsive to conventional therapy, including systemic antibiotics (FDA approved in ages ≥12 years and adults); has also been used for the treatment of moderate acne and high-risk neuroblastoma

Medication Guide Available

Yes

Pregnancy Risk Factor

X

Pregnancy Considerations

Isotretinoin and its metabolites can be detected in fetal tissue following maternal use during pregnancy (Benifla 1995; Kraft 1989). [US Boxed Warnings]: Use of isotretinoin is contraindicated in females who are or may become pregnant. Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy and the risk for severe birth defects is high, with any dose or even with short treatment duration. Low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased. Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE™ risk evaluation and mitigation strategy (REMS) program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug. If pregnancy occurs during therapy, isotretinoin should be discontinued immediately and the patient referred to an obstetrician-gynecologist specializing in reproductive toxicity. This medication is contraindicated in females of childbearing potential unless they are able to comply with the guidelines of the iPLEDGE™ pregnancy prevention program. Females of childbearing potential must have two negative pregnancy tests with a sensitivity of at least 25 milliunits/mL prior to beginning therapy and testing should continue monthly during therapy. Females of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of isotretinoin. Upon discontinuation of treatment, females of childbearing potential should have a pregnancy test after their last dose and again one month after their last dose. Two forms of contraception should be continued during this time. Any pregnancies should be reported to the iPLEDGE™ program (www.ipledgeprogram.com or 866-495-0654) and the FDA through MedWatch (800-FDA-1088).

Breast-Feeding Considerations

It is not known if isotretinoin is present in breast milk. A case report describes a green discharge from the breast of a nonbreastfeeding woman that was determined to be iatrogenic galactorrhea due to isotretinoin (Larsen 1985). Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.

Contraindications

Hypersensitivity to isotretinoin or any component of the formulation; sensitivity to parabens (Zenatane only) or vitamin A; pregnant women or those who may become pregnant

Canadian labeling: Additional contraindications not in the US labeling: Breastfeeding, hepatic or renal insufficiency, hypervitaminosis A, excessive hyperlipidemia, concurrent tetracycline therapy.

Documentation of allergenic cross-reactivity for retinoids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

This medication should only be prescribed by prescribers competent in treating severe recalcitrant nodular acne and experienced with the use of systemic retinoids. Anaphylaxis and other types of allergic reactions, including cutaneous reactions and serious cases of allergic vasculitis, often with purpura of the extremities and extracutaneous involvement (including renal) have been reported. Discontinue therapy if a serious allergic reaction occurs and institute appropriate medical management. [US Boxed Warnings]: Birth defects (facial, eye, ear, skull, central nervous system, cardiovascular, thymus and parathyroid gland abnormalities) have been noted following isotretinoin exposure during pregnancy and the risk for severe birth defects is high, with any dose or even with short treatment duration. Low IQ scores have also been reported. The risk for spontaneous abortion and premature births is increased. Because of the high likelihood of teratogenic effects, all patients (male and female), prescribers, wholesalers, and dispensing pharmacists must register and be active in the iPLEDGE risk evaluation and mitigation strategy (REMS) program; do not prescribe isotretinoin for women who are or who are likely to become pregnant while using the drug. If pregnancy occurs during therapy, isotretinoin should be discontinued immediately and the patient referred to an obstetrician-gynecologist specializing in reproductive toxicity (see Additional Information or Pharmacotherapy Pearls for details). Women of childbearing potential must be capable of complying with effective contraceptive measures. Patients must select and commit to two forms of contraception. Therapy is begun after two negative pregnancy tests; effective contraception must be used for at least 1 month before beginning therapy, during therapy, and for 1 month after discontinuation of therapy. Prescriptions should be written for no more than a 30-day supply, and pregnancy testing and counseling should be repeated monthly.

May cause depression, psychosis, mood disturbance, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. All patients should be observed closely for symptoms of depression or suicidal thoughts. Discontinue therapy if depression, mood disturbance, psychosis, or aggression develops. Discontinuation of treatment alone may not be sufficient, further evaluation may be necessary. Use with extreme caution in patients with a history of psychiatric disorder. Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances; discontinue immediately and refer patient to a neurologist if papilledema occurs. Hearing impairment, which can continue after therapy is discontinued, may occur. Clinical hepatitis, elevated liver enzymes, inflammatory bowel disease, skeletal hyperostosis, premature epiphyseal closure, vision impairment, corneal opacities, decreased tolerance to contact lenses (due to dry eyes), and decreased night vision have also been reported with the use of isotretinoin. Postmarketing reports of erythema multiforme and severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities, have been reported; monitor for severe skin reactions; discontinue use if severe skin reaction occurs.

Use with caution in patients with diabetes mellitus; impaired glucose control has been reported. Acute pancreatitis may occur in patients with normal or elevated triglyceride levels; fatal hemorrhagic pancreatitis (rare) has been reported; discontinue therapy if hypertriglyceridemia cannot be controlled at an acceptable level or symptoms of pancreatitis occur. Marked elevations of serum triglycerides have been reported; use with caution in patients with hypertriglyceridemia or those who may be at high risk (eg, patients with diabetes, obesity, increased alcohol intake, family history of or those with lipid metabolism disorder). The effects on triglycerides, HDL, and cholesterol have been reversible upon discontinuation of therapy. Instruct patients to avoid or limit ethanol; may increase triglyceride levels if taken in excess.

May decrease bone mineral density; osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been reported. Use caution in patients with a genetic predisposition for bone loss (eg, age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia or other disorders of bone metabolism; including patients diagnosed with anorexia nervosa and those on concomitant medications that may cause drug-induced osteoporosis/osteomalacia and/or affect vitamin D metabolism (eg, systemic corticosteroids, anticonvulsants). Patients may be at increased risk when participating in activities with repetitive impact (such as sports) where the risk of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. Patients should be instructed not to donate blood during therapy and for 1 month following discontinuation of therapy due to risk of donated blood being given to a pregnant female. Safety of long-term use is not established and is not recommended; the effect on bone loss is unknown. Some products may contain tartrazine (FD&C yellow no. 5), which may cause allergic reactions, including bronchial asthma, in certain individuals. Allergy is frequently seen in patients who also have an aspirin hypersensitivity.

Absorica: Absorption is ~83% greater than Accutane when administered under fasting conditions; they are bioequivalent when taken with a high-fat meal. Absorica is not interchangeable with other generic isotretinoin products. Isotretinoin and tretinoin (which is also known as all-trans retinoic acid, or ATRA) may be confused, while both products may be used in cancer treatment, they are not interchangeable; verify product prior to dispensing and administration to prevent medication errors.

Musculoskeletal symptoms (including arthralgia) have been reported; generally symptoms were mild to moderate, but occasionally required discontinuation of therapy. Transient pain in the chest has occurred; symptoms generally cleared after discontinuation of therapy, but in some cases persisted. Rhabdomyolysis, some associated with strenuous physical activity, has been reported (rarely).

Acute pancreatitis may occur in patients with normal or elevated triglyceride levels; fatal hemorrhagic pancreatitis (rare) has been reported; discontinue therapy if hypertriglyceridemia cannot be controlled at an acceptable level or symptoms of pancreatitis occurs. Neutropenia and rare cases of agranulocytosis have been reported; discontinue if clinically significant decreases in white cell counts occur. Avoid prolonged exposure to UV rays or sunlight. Avoid skin resurfacing procedures (eg, dermabrasion, laser) and wax epilation during therapy and for at least 6 months after discontinuation of isotretinoin due to the risk of scarring. Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.

Warnings: Additional Pediatric Considerations

Children may experience a higher frequency of some adverse effects including arthralgia (22%) and back pain (29%).

Adverse Reactions

Cardiovascular: Cerebrovascular accident, chest pain, edema, flushing, palpitations, syncope, tachycardia, thrombosis

Central nervous system: Aggressive behavior, attempted suicide, depression, dizziness, drowsiness, emotional lability, fatigue, headache, insomnia, lethargy, malaise, nervousness, paresthesia, pseudotumor cerebri, psychosis, seizure, suicidal ideation, vasculitis (renal), violent behavior

Dermatologic: Acne fulminans, allergic skin reaction, alopecia, cheilitis, diaphoresis, eczema, eruptive xanthoma, facial erythema, hair disease, hirsutism, hyperpigmentation, hypopigmentation, nail disease, paronychia, pruritus, pyogenic granuloma, scaling of skin of feet, skin atrophy, skin photosensitivity, skin rash, sunburn (increased susceptibility), superficial peeling of palms, xeroderma

Endocrine & metabolic: Decreased HDL cholesterol, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum cholesterol, increased serum glucose, increased serum triglycerides, hyperuricemia, menstrual disease, weight loss

Gastrointestinal: Colitis, esophagitis, esophageal ulcer, gastrointestinal symptoms (nonspecific), gingival hemorrhage, gingivitis, inflammatory bowel disease, nausea, pancreatitis, xerostomia

Genitourinary: Genitourinary disease (nonspecific findings), hematuria, proteinuria, pyuria

Hematologic & oncologic: Anemia, bruise, lymphadenopathy, neutropenia, purpura, thrombocytopenia

Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST, hepatitis

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Infection: Herpes simplex infection (disseminated), infection

Neuromuscular & skeletal: Arthralgia, arthritis, back pain (children), bone disease, calcification of ligament, calcification of tendon, decreased bone mineral density, increased creatine phosphokinase, myalgia, premature epiphyseal closure, skeletal hyperostosis, tendonitis, weakness

Ophthalmic: Blepharitis, cataract, chalazion, conjunctivitis, corneal opacity, hordeolum, keratitis, nocturnal amblyopia, optic neuritis, photophobia, vision color changes, visual disturbance

Otic: Auditory impairment, tinnitus

Renal: Glomerulonephritis

Respiratory: Bronchospasm, dry nose, epistaxis, respiratory tract infection, voice disorder, Wegener's granulomatosis

Miscellaneous: Wound healing impairment

Rare but important or life-threatening: Agranulocytosis, contact lens intolerance, decreased visual acuity, dry eye syndrome, erythema multiforme, eye pain, eyelid disease (meibomian gland dysfunction/atrophy; Neudorfer 2012), myopia, rhabdomyolysis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Metabolism/Transport Effects

None known.

Drug Interactions

Avoid Concomitant Use

Avoid concomitant use of ISOtretinoin with any of the following: Aminolevulinic Acid (Systemic); Multivitamins/Fluoride (with ADE); Multivitamins/Minerals (with ADEK, Folate, Iron); Multivitamins/Minerals (with AE, No Iron); Tetracyclines; Vitamin A

Increased Effect/Toxicity

ISOtretinoin may increase the levels/effects of: Aminolevulinic Acid (Systemic); Aminolevulinic Acid (Topical); Mipomersen; Porfimer; Verteporfin

The levels/effects of ISOtretinoin may be increased by: Alcohol (Ethyl); Multivitamins/Fluoride (with ADE); Multivitamins/Minerals (with ADEK, Folate, Iron); Multivitamins/Minerals (with AE, No Iron); Tetracyclines; Vitamin A

Decreased Effect

ISOtretinoin may decrease the levels/effects of: Estrogen Derivatives (Contraceptive); Progestins (Contraceptive)

Food Interactions

Isotretinoin bioavailability increased if taken with food or milk. Management: Administer orally with a meal (except Absorica which may be taken without regard to meals).

Hazardous Drugs Handling Considerations

Hazardous agent (meets NIOSH 2016 criteria). This medication is not on the NIOSH (2016) list; however, it meets the criteria for a hazardous drug. Drugs are classified as hazardous based on their properties; the properties of a hazardous drug include one or more of the following characteristics: carcinogenic, teratogenic (or other developmental toxicity), reproductive toxicity, organotoxic at low doses, genotoxic, and/or new agents with structural or toxicity profiles similar to existing hazardous agents.

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016).

Storage/Stability

Store at 20°C to 25°C (68°F to 77° F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light.

Mechanism of Action

Reduces sebaceous gland size and reduces sebum production in acne treatment; in neuroblastoma, decreases cell proliferation and induces differentiation

Pharmacodynamics/Kinetics (Adult data unless noted)

Note: Pharmacokinetic parameters in adolescents (12 to 15 years) are similar to adults.

Absorption: Enhanced with a high-fat meal; Absorica absorption is ~83% greater than Accutane when administered under fasting conditions; they are bioequivalent when taken with a high-fat meal.

Protein binding: 99% to 100%; primarily albumin

Metabolism: Hepatic via CYP2B6, 2C8, 2C9, 3A4; forms metabolites; major metabolite: 4-oxo-isotretinoin (active)

Half-life elimination: Terminal: Parent drug: 21 hours; Metabolite: 21 to 24 hours

Time to peak, serum: 3 to 5 hours

Excretion: Urine and feces (equal amounts)

Dosing: Usual

Pediatric:

Acne vulgaris, severe recalcitrant nodular: Children ≥12 years and Adolescents: Oral: 0.5 to 1 mg/kg/day in 2 divided doses; for severe cases (involving trunk, nuchal region, lower back, buttocks, thighs) may require higher doses up to 2 mg/kg/day in 2 divided doses. Duration of therapy is typically 15 to 20 weeks or until the total cyst count decreases by 70%, whichever is sooner; an alternate reported approach is continuation until a total cumulative dose of 120 mg/kg (eg, 1 mg/kg/day for 120 days). An initial dose of ≤0.5 mg/kg/day may be used to minimize initial flaring (Strauss 2007)

Acne vulgaris, moderate: Limited data available: Children ≥12 years and Adolescents: 20 mg/day (~0.3 to 0.5 mg/kg/day) continued for 6 to 12 months to cumulative dose 120 mg/kg has been shown effective (Amichai 2006)

Neuroblastoma, maintenance: Infants, Children, and Adolescents: Oral: 80 mg/m2/dose every 12 hours for the last 2 weeks (14 consecutive days) of a 4-week cycle for 6 cycles; dinutuximab therapy is administered during the first week of the 4-week cycle (Yu 2010); begin after continuation chemotherapy or transplantation (Matthay 1999)

Adult: Acne vulgaris: Oral: 0.5 to 1 mg/kg/day in 2 divided doses for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever is sooner. Adults with very severe disease/scarring or primarily involves the trunk may require dosage adjustment up to 2 mg/kg/day. A second course of therapy may be initiated after a period of ≥2 months of therapy. An initial dose of ≤0.5 mg/kg/day may be used to minimize initial flaring (Strauss 2007).

Dosing adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing adjustment in hepatic impairment: Children, Adolescents, and Adults:

Hepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer’s labeling.

Hepatotoxicity during treatment: Liver enzymes may normalize with dosage reduction or with continued treatment; discontinue if normalization does not readily occur or if hepatitis is suspected.

Administration

Oral: Administer orally with a meal (except Absorica, which may be taken without regard to meals). According to the manufacturers’ labeling, capsules should be swallowed whole with a full glass of liquid. For patients unable to swallow capsule whole, an oral liquid may be prepared; may irritate esophagus if contents are removed from the capsule. In pediatric neuroblastoma trial when patient was unable to swallow capsule, the end of capsule was punctured/cut and capsules contents extruded into ice cream or yogurt (high-fat food); if capsule is opened, contents must be consumed immediately to avoid degradation of the drug (Matthay 1999; Veal 2007).

Monitoring Parameters

CBC with differential and platelet count, baseline sedimentation rate, glucose, CPK; signs of depression, mood alteration, psychosis, aggression, severe skin reactions

Pregnancy test (for all female patients of childbearing potential): Two negative tests with a sensitivity of at least 25 mIU/mL prior to beginning therapy (the second performed at least 19 days after the first test and performed during the first 5 days of the menstrual period immediately preceding the start of therapy); monthly tests to rule out pregnancy prior to refilling prescription

Lipids: Prior to treatment and at weekly or biweekly intervals until response to treatment is established. Test should not be performed <36 hours after consumption of ethanol.

Liver function tests: Prior to treatment and at weekly or biweekly intervals until response to treatment is established.

Dosage Forms

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

Capsule, Oral:

Absorica: 10 mg, 20 mg [contains soybean oil]

Absorica: 25 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #6 (sunset yellow), soybean oil, tartrazine (fd&c yellow #5)]

Absorica: 30 mg [contains soybean oil]

Absorica: 35 mg [contains fd&c blue #2 (indigotine), soybean oil]

Absorica: 40 mg [contains soybean oil]

Amnesteem: 10 mg, 20 mg, 40 mg [contains soybean oil]

Claravis: 10 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Claravis: 20 mg [contains soybean oil]

Claravis: 30 mg

Claravis: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Myorisan: 10 mg, 20 mg [contains soybean oil]

Myorisan: 30 mg

Myorisan: 40 mg [contains fd&c yellow #6 (sunset yellow), soybean oil]

Zenatane: 10 mg [contains brilliant blue fcf (fd&c blue #1), edetate disodium, fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

Zenatane: 20 mg [contains edetate disodium, methylparaben, propylparaben, soybean oil]

Zenatane: 30 mg [contains edetate disodium, fd&c blue #2 aluminum lake, fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

Zenatane: 40 mg [contains brilliant blue fcf (fd&c blue #1), edetate disodium, fd&c blue #2 (indigotine), fd&c yellow #10 (quinoline yellow), methylparaben, propylparaben, soybean oil]

Extemporaneous Preparations

For patients unable to swallow the capsules whole, an oral liquid may be prepared with softgel capsules (not recommended by the manufacturers) by one of the following methods:

Place capsules (softgel formulations only) in small container and add warm (~37°C [97°F]) water or milk to cover capsule(s); wait 2 to 3 minutes until capsule is softened and then drink the milk or water with the softened capsule, or swallow softened capsule.

Puncture capsule (softgel formulations only) with needle or cut with scissors; squeeze capsule contents into 5 to 10 mL of milk or tube feed formula; draw mixture up into oral syringe and administer via feeding tube; flush feeding tube with ≥30 mL additional milk or tube feeding formula.

Puncture capsule (softgel formulations only) with needle or cut with scissors and draw contents into oral syringe; add 1 to 5 mL of medium chain triglyceride, soybean, or safflower oil to the oral syringe; mix gently and administer via feeding tube; flush feeding tube with ≥30 mL milk or tube feeding formula.

Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-192.

Cephalexin – October 2017

The Pronunciation, Medication Safety Issues, Generic Availability (US), Pregnancy Risk Factor, Dosing: Usual, Test Interactions and Dosage Forms fields were omitted from the Cephalexin monograph in the Pediatric & Neonatal Dosage Handbook 24th edition during the pagination process.

Fields that were omitted from the print edition are highlighted below:

Cephalexin (sef a LEKS in)

Medication Safety Issues

Sound-alike/look-alike issues:

Cephalexin may be confused with cefaclor, ceFAZolin, ciprofloxacin

Keflex may be confused with Keppra, Valtrex

Related Information

  • Prevention of Infective Endocarditis
  • Relative Infant Dose

Brand Names: US

  • Daxbia
  • Keflex

Brand Names: Canada

  • Apo-Cephalex
  • Dom-Cephalexin
  • Keflex
  • PMS-Cephalexin
  • Teva-Cephalexin

Index Terms

  • Cephalexin Monohydrate

Therapeutic Category

  • Antibiotic, Cephalosporin (First Generation)

Generic Availability (US)

Yes

Use

Treatment of susceptible bacterial infections, including acute otitis media and infections of the respiratory tract, skin and skin structure, bone, and genitourinary tract (FDA approved in pediatric patients [age not specified] and adults); has also been used as alternate therapy for endocarditis prophylaxis

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Cephalexin crosses the placenta and produces therapeutic concentrations in the fetal circulation and amniotic fluid (Creatsas 1980). Peak concentrations in pregnant patients are similar to those in nonpregnant patients. Prolonged labor may decrease oral absorption (Griffith 1983; Paterson 1972).

Breast-Feeding Considerations

Cephalexin is excreted in breast milk.

The relative infant dose (RID) of cephalexin is 0.13% to 0.52% when compared to an infant therapeutic dose of 25 to 100 mg/kg/day. In general, breastfeeding is considered acceptable when the relative infant dose is <10%; when an RID is >25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000). Using a milk concentration of 0.85 mcg/mL, the estimated daily infant dose via breast milk is 0.13 mg/kg/day. This milk concentration was obtained following a single maternal dose of cephalexin 1,000 mg orally on the third postpartum day (Kafetzis 1981).

The mean peak milk concentration occurred 4 to 5 hours after the dose (Kafetzis 1981). Slightly higher concentrations of cephalexin were detected in the breast milk of a lactating woman also administered probenecid and cephalexin for ≥16 days (Ilett 2006).

Diarrhea has been reported in breastfeeding infants (Ilett 2006; Ito 1993). In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances (WHO 2002).

When an antibiotic is needed, cephalexin may be used to treat mastitis in breastfeeding women allergic to preferred agents (Amir 2014; Berens 2015). The manufacturer recommends that caution be exercised when administering cephalexin to nursing women.

Contraindications

Hypersensitivity to cephalexin, other cephalosporins, or any component of the formulation

Warnings/Precautions

Allergic reactions (eg, rash, urticaria, angioedema, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [TEN]) have been reported. If an allergic reaction occurs, discontinue immediately and institute appropriate treatment. Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures. Modify dosage in patients with severe renal impairment. Use with caution in patients with a history of penicillin allergy, especially IgE-mediated reactions (eg, anaphylaxis, urticaria). Positive direct Coombs tests and acute intravascular hemolysis has been reported. If anemia develops during or after therapy, discontinue use and work up for drug-induced hemolytic anemia. Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. May be associated with increased INR, especially in nutritionally-deficient patients, prolonged treatment, hepatic or renal disease. Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.

Adverse Reactions

Central nervous system: Agitation, confusion, dizziness, fatigue, hallucination, headache

Dermatologic: Erythema multiforme (rare), genital pruritus, skin rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare), urticaria

Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, gastritis, nausea (rare), pseudomembranous colitis, vomiting (rare)

Genitourinary: Genital candidiasis, vaginal discharge, vaginitis

Hematologic & oncologic: Eosinophilia, hemolytic anemia, neutropenia, thrombocytopenia

Hepatic: Cholestatic jaundice (rare), hepatitis (transient, rare), increased serum ALT, increased serum AST

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Neuromuscular & skeletal: Arthralgia, arthritis, arthropathy

Renal: Interstitial nephritis (rare)

Metabolism/Transport Effects

None known.

Drug Interactions

Avoid Concomitant Use

Avoid concomitant use of Cephalexin with any of the following: BCG (Intravesical); Cholera Vaccine

Increased Effect/Toxicity

Cephalexin may increase the levels/effects of: MetFORMIN; Vitamin K Antagonists

The levels/effects of Cephalexin may be increased by: Probenecid

Decreased Effect

Cephalexin may decrease the levels/effects of: BCG (Intravesical); BCG Vaccine (Immunization); Cholera Vaccine; Lactobacillus and Estriol; Sodium Picosulfate; Typhoid Vaccine

The levels/effects of Cephalexin may be decreased by: Multivitamins/Minerals (with ADEK, Folate, Iron); Multivitamins/Minerals (with AE, No Iron); Zinc Salts

Food Interactions

Peak antibiotic serum concentration is lowered and delayed, but total drug absorbed is not affected. Cephalexin serum levels may be decreased if taken with food. Management: Administer without regard to food.

Storage/Stability

Capsule: Store at 25°C (77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).

Powder for oral suspension: Store at 20°C to 25°C (68°F to 77°F). Refrigerate after reconstitution; discard after 14 days.

Tablet: Store at 20°C to 25°C (68°F to 77°F).

Mechanism of Action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Pharmacodynamics/Kinetics (Adult data unless noted)

Absorption: Rapid (90%); delayed in young children and may be decreased up to 50% in neonates

Distribution: Widely into most body tissues and fluids, including gallbladder, liver, kidneys, bone, sputum, bile, and pleural and synovial fluids; CSF penetration is poor

Protein binding: 6% to 15%

Half-life elimination: Neonates: 5 hours; Children 3-12 months: 2.5 hours; Adults: 0.5 to 1.2 hours (prolonged with renal impairment)

Time to peak, serum: ~1 hour

Excretion: Urine (80% to 100% as unchanged drug) within 8 hours

Dosing: Usual

Pediatric:

General dosing, susceptible infection: Infants, Children, and Adolescents:

Mild to moderate infection: Oral: 25 to 50 mg/kg/day divided every 6 or 12 hours; maximum daily dose: 2,000 mg/day (Red Book [AAP 2015])

Severe infection: Oral: 75 to 100 mg/kg/day divided every 6 to 8 hours; maximum daily dose: 4,000 mg/day (Bradley, 2015; Red Book [AAP 2015])

Catheter (peritoneal dialysis); exit-site or tunnel infection: Limited data available: Infants, Children, and Adolescents: Oral: 10 to 20 mg/kg/day once daily or divided into 2 doses; maximum dose: 1,000 mg/dose (Warady [ISPD] 2012)

Pharyngitis/tonsillitis (group A streptococcal):

Manufacturer's labeling: Note: Experts recommend dosing on the higher end of the presented range (IDSA [Shulman 2012])

Children and Adolescents <15 years: Oral: 25 to 50 mg/kg/day divided every 12 hours; maximum dose: 500 mg/dose

Adolescents ≥15 years: Oral: 500 mg every 12 hours

Alternate dosing: IDSA recommendation: Infants, Children, and Adolescents: Oral: 20 mg/kg/dose twice daily for 10 days, maximum dose: 500 mg/dose (IDSA [Shulman 2012])

Impetigo (staphylococcus or streptococcus): Infants, Children, and Adolescents: Oral: 25 to 50 mg/kg/day divided every 6 or 8 hours; maximum dose: 250 mg/dose; continue for at least 7 days, full duration dependent upon clinical response (IDSA [Stevens 2014])

Otitis media, acute (AOM): Infants and Children: Oral: 75 to 100 mg/kg/day divided every 6 hours; maximum dose not established for AOM; usual maximum adult dose for mild to moderate infections: 500 mg/dose and for severe infections: 1,000 mg/dose. Note: Cephalexin is not routinely recommended as an empiric treatment option (AAP [Lieberthal 2013]).

Skin and skin structure infections (eg, cellulitis, erysipelas):

Manufacturer's labeling:

Infants, Children, and Adolescents ≤15 years: Oral: 25 to 50 mg/kg/day divided every 12 hours, maximum dose: 500 mg/dose; for ß-hemolytic streptococcal infections, a duration of 10 days is suggested

Adolescents >15 years: 500 mg every 12 hours

Alternate dosing: IDSA recommendations: Infants, Children, and Adolescents: Oral: 25 to 50 mg/kg/day divided every 6 hours; maximum dose: 500 mg/dose; continue for at least 5 days or longer depending upon clinical response (IDSA [Stevens 2014])

Endocarditis; prophylaxis (dental, oral, or respiratory tract procedures): Infants, Children, and Adolescents: Oral: 50 mg/kg administered 30 to 60 minutes prior to procedure; maximum dose: 2,000 mg/dose (AHA [Wilson 2007]). Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur (AHA [Wilson 2007]).

Pneumonia, community-acquired: S. aureus (methicillin-susceptible), mild infection or step-down therapy: Infants >3 months, Children, and Adolescents: Oral: 75 to 100 mg/kg/day in 3 to 4 divided doses; maximum daily dose: 4,000 mg/day (IDSA/PIDS [Bradley 2011])

Urinary tract infection, treatment: Oral:

Infants and Children 2 months to 2 years: Empiric therapy in febrile patients: 50 to 100 mg/kg/day divided every 6 hours for 7 to 14 days (AAP 2011)

Adolescents >15 years: Uncomplicated cystitis: 500 mg every 12 hours for 7 to 14 days

Osteoarticular infection (eg, septic arthritis, osteomyelitis); step-down therapy: Infants, Children, and Adolescents: Oral: 100 mg/kg/day divided every 6 to 8 hours; maximum daily dose: 4,000 mg/day; duration of therapy variable, dependent upon clinical response and typically extensive (weeks of therapy); compliance should be monitored (Bradley 2015; Red Book [AAP 2015]); a small (n=11) prospective, open-label pharmacokinetic study reported a median dose of 40 mg/kg/dose every 8 hours (mean age: 7 years; range: 1 to 16 years; dose range: 19 to 51 mg/kg/dose every 8 hours) maintained serum concentrations long enough to meet the pharmacokinetic/pharmacodynamic target for efficacy (T>MIC ≥ 40%) (Autmizguine 2013)

Adult:

General dosing, susceptible infection: Oral: 250 to 1,000 mg every 6 hours; maximum daily dose: 4,000 mg/day

Indication-specific dosing:

Impetigo: Oral: 250 mg every 6 hours; continue for 7 days, depending upon clinical response (IDSA [Stevens 2014])

Pharyngitis/tonsillitis (group A streptococcal): Oral: 500 mg every 12 hours. Note: IDSA recommends a duration of 10 days (IDSA [Shulman 2012])

Skin and skin structure infections: Oral: 500 mg every 12 hours

Urinary tract infection (uncomplicated cystitis): Oral: 500 mg every 12 hours for 7 to 14 days

Endocarditis, prophylaxis (dental, oral, or respiratory tract procedures): Oral: 2,000 mg 30 to 60 minutes prior to procedure. Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur.

Dosing adjustment in renal impairment:

Infants, Children, and Adolescents: There are no recommendations in the manufacturer's labeling; the following adjustments have been recommended (Aronoff 2007). Note: Renally adjusted dose recommendations are based on doses of 25 to 50 mg/kg/day divided every 6 hours: Oral:

CrC l> 50 mL/minute/1.73 m2: No adjustment necessary

CrCl 30-50 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 8 hours (maximum dose: 500 mg/dose)

CrCl 10-29 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 12 hours (maximum dose: 500 mg/dose)

CrCl < 10 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 24 hours (maximum dose: 500 mg/dose)

Intermittent hemodialysis: 5 to 10 mg/kg/dose every 24 hours after dialysis (maximum dose: 500 mg/dose)

Peritoneal dialysis: 5 to 10 mg/kg/dose every 24 hours (maximum dose: 500 mg/dose)

Adults:

CrCl > 50 mL/minute: No adjustment necessary

CrCl 10 to 50 mL/minute: 250 to 500 mg every 8 to 12 hours

CrCl <10: 250 to 500 mg every 12 to 24 hours

Hemodialysis: 250 mg every 12 to 24 hours; moderately dialyzable (20% to 50%); give dose after dialysis session

Dosing adjustment in hepatic impairment: There are no dosing adjustments provided in the manufacturer's labeling.

Preparation for Administration

Oral: Powder for oral suspension: Reconstitute powder for oral suspension with appropriate amount of water as specified on the bottle. Shake vigorously until suspended.

Administration

Oral: Shake suspension well before use. Take without regard to food. If GI distress, may take with food. Give around-the-clock to promote less variation in peak and trough serum levels.

Monitoring Parameters

With prolonged therapy, monitor renal, hepatic, and hematologic function periodically; monitor for signs of anaphylaxis with first few doses; number and type of stools/day for diarrhea

Test Interactions

Positive direct Coombs', false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest®, Fehling's solution), false-positive serum or urine creatinine with Jaffé reaction, false-positive urinary proteins and steroids

Dosage Forms

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

Capsule, Oral:

Daxbia: 333 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Keflex: 250 mg, 500 mg, 750 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Generic: 250 mg, 500 mg, 750 mg

Suspension Reconstituted, Oral:

Generic: 125 mg/5 mL (100 mL, 200 mL); 250 mg/5 mL (100 mL, 200 mL)

Tablet, Oral:

Generic: 250 mg, 500 mg

Ertapenem – October 2017

Revision in the Dosing: Usual field of the Ertapenem monograph in the Pediatric and Neonatal Lexi-Drugs database, available online and in mobile apps.

The monograph previously read:

Dosing: Usual (only portion of field impacted is presented):

Surgical prophylaxis: Children and Adolescents: IV: 5 mg/kg 60 minutes before procedure; maximum dose: 1,000 mg (Bratzler 2013)

It has been revised to read:

Dosing: Usual (only portion of field impacted is presented):

Surgical prophylaxis: Children and Adolescents: IV: 15 mg/kg 60 minutes before procedure; maximum dose: 1,000 mg (Bratzler 2013)

These changes have been automatically posted to online and mobile app databases.

Phenytoin – June 2017

Revision in the Dosing: Obesity field of the Phenytoin monograph in the Lexi-Drugs database, available online and in mobile apps, as well as the following print publications: Drug Information Handbook 25th and 26th editions; Drug Information Handbook with International Trade Names Index 25th and 26th editions; Geriatric Dosage Handbook 21st edition; Drug Information Handbook for Dentistry 22nd and 23rd editions

The monograph previously read:

Dosing: Obesity (only portion of field impacted is presented):

May also target a specific concentration (eg, 15 to 20 mg/L) by using the Vd obtained from patients with obesity (Abernethy 1985; Burton 2006). Therefore, the concentration desired (in mg/L) may be multiplied by this Vd (obesity) (in L) which is determined using the patient’s total and ideal body weights.

Vd (obesity) = 0.65 L/kg (IBW) + 1.33 (TBW – IBW)

Loading dose = Calculated Vd (obesity) (target concentration)

For example: For a patient with a total body weight (TBW) of 300 lb (136 kg) and an IBW of 73 kg

Vd (obesity) = 0.65 L/kg (73 kg) + 1.33 (136 kg – 73 kg) = 131 L; then,

Loading dose = 131 L x 15 mg/L = 1,965 mg

It has been revised to read:

Dosing: Obesity (only portion of field impacted is presented):

May also target a specific concentration (eg, 15 to 20 mg/L) by using the Vd obtained from patients with obesity (Abernethy 1985; Burton 2006). Therefore, the concentration desired (in mg/L) may be multiplied by this Vd (obesity) (in L) which is determined using the patient’s total and ideal body weights.

Vd (obesity) = 0.65 L/kg [(IBW) + 1.33 (TBW – IBW)]

Loading dose = Calculated Vd (obesity) (target concentration)

For example: For a patient with a total body weight (TBW) of 300 lb (136 kg) and an IBW of 73 kg

Vd (obesity) = 0.65 L/kg [(73 kg) + 1.33 (136 kg – 73 kg)] = 101.9 L; then,

Loading dose = 101.9 L x 15 mg/L = 1,529 mg

These changes have been automatically posted to online and mobile app databases.

Sulfamethoxazole/Trimethoprim Injection – April 2017

Revision in the Dosage: Renal function impairment field of the Sulfamethoxazole/Trimethoprim Injection monograph in the Drug Facts and Comparisons database, available online and in the print publication Drug Facts and Comparisons, 2015, 2016 and 2017; and the loose-leaf edition beginning with the September 2014 update through October 2016.

The monograph previously read:

Dosage: Renal function impairment (only the portion of field impacted is presented):

P. jiroveci pneumonia treatment

Adults

Creatinine clearance less than 10 mL/minute

Trimethoprim 5 mg/kg IV every 12 hours

It has been revised to read:

Dosage: Renal function impairment (only the portion of field impacted is presented):

P. jiroveci pneumonia treatment

Adults

Creatinine clearance less than 10 mL/minute

Trimethoprim 5 mg/kg IV every 24 hours

Penicillin G (Parenteral/Aqueous) – March 2017

Revision in the Dosing: Adult field of the Penicillin G (Parenteral/Aqueous) monograph in the Lexi-Drugs database, available online, in mobile apps and in the print publication Drug Information Handbook, 26th edition (in press).

The monograph previously read:

Dosing: Adult (only the portion of the field that is impacted is presented):

Endocarditis, treatment: IV:

Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 6 hours with concomitant gentamicin.

Enterococcus, native or prosthetic valve (penicillin-susceptible/streptomycin-susceptible/gentamicin-resistant strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 6 hours with concomitant streptomycin.

It has been revised to read:

Dosing: Adult (only the portion of the field that is impacted is presented):

Endocarditis, treatment: IV:

Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 4 hours with concomitant gentamicin.

Enterococcus, native or prosthetic valve (penicillin-susceptible/streptomycin-susceptible/gentamicin-resistant strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 4 hours with concomitant streptomycin.

These changes have been posted to online and mobile app databases. (Please update your Lexi-Drugs mobile application to get this updated dosing.)

Revision in the Dosing: Usual field (adult dosing) of the Penicillin G (Parenteral/Aqueous) monograph in the Pediatric and Neonatal Lexi-Drugs database, available online and in mobile apps.

The monograph previously read:

Dosing: Usual [adult dosing] (only the portion of the field that is impacted is presented)

Endocarditis, treatment (AHA [Baddour 2015): IV:

Enterococcus: IV: 18 to 30 million units/day as continuous infusion or in divided doses every 6 hours; use in combination with other antibiotics based on susceptibility.

It has been revised to read:

Dosing: Usual [adult dosing] (only the portion of the field that is impacted is presented)

Endocarditis, treatment (AHA [Baddour 2015): IV:

Enterococcus: IV: 18 to 30 million units/day as continuous infusion or in divided doses every 4 hours; use in combination with other antibiotics based on susceptibility.

These changes have been posted to online and mobile app databases. (Please update your Pediatric and Neonatal Lexi-Drugs mobile application to get this updated dosing.)

Penicillin G Sodium Injection and Penicillin G Potassium Injection – March 2017

Revision in the Dosing: Adult field of the Penicillin G Sodium and Penicillin G Potassium Injection monographs in the Facts & Comparisons eAnswers database.

The monograph previously read:

Dosing: Adult (only the portion of the field that is impacted is presented):

Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains)

18 to 30 million units/day IV as continuous infusion or in divided doses every 6 hours with concomitant gentamicin.

Enterococcus, native or prosthetic valve (penicillin-susceptible/streptomycin-susceptible/gentamicin-resistant strains)

18 to 30 million units/day IV as continuous infusion or in divided doses every 6 hours with concomitant streptomycin.

It has been revised to read:

Dosing: Adult (only the portion of the field that is impacted is presented):

Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains)

18 to 30 million units/day IV as continuous infusion or in divided doses every 4 hours with concomitant gentamicin.

Enterococcus, native or prosthetic valve (penicillin-susceptible/streptomycin-susceptible/gentamicin-resistant strains)

18 to 30 million units/day IV as continuous infusion or in divided doses every 4 hours with concomitant streptomycin.

These changes have been posted to the online database.