Skip to Content

Nerlynx

Generic Name: Neratinib Maleate
Class: Antineoplastic Agents
Chemical Name: (E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
Molecular Formula: C30H29ClN6O3
CAS Number: 698387-09-6

Medically reviewed on Sep 10, 2018

Introduction

Antineoplastic agent; a potent, selective, and irreversible inhibitor of human epidermal growth factor receptor type 2 (HER2), HER4, and epidermal growth factor receptor (EGFR) tyrosine kinases.1 8

Uses for Nerlynx

Breast Cancer

Single-agent therapy for extended adjuvant treatment of HER2-positive, early-stage breast cancer in patients treated with adjuvant trastuzumab therapy.1 2 Subgroup analysis suggests a greater effect on invasive disease-free survival in patients with hormone receptor-positive disease, those treated with sequential adjuvant trastuzumab therapy, and those who completed adjuvant trastuzumab therapy within 1 year of randomization.1

Nerlynx Dosage and Administration

General

Antidiarrheal Prophylaxis

  • To minimize incidence and severity of treatment-related diarrhea, initiate prophylaxis with loperamide during cycles 1–2.1 Administer loperamide hydrochloride 4 mg 3 times daily during weeks 1–2 (days 1–14), twice daily during weeks 3–8 (days 15–56), and then as needed until stool frequency decreases to 1–2 per day; dosages >16 mg daily not recommended.1 (See Diarrhea Under Cautions.)

Restricted Distribution Program

  • Must obtain neratinib through specialty pharmacies.3

  • Consult Nerlynx website ([Web]) for specific ordering and availability information.3

Administration

Oral Administration

Administer orally once daily with food at approximately the same time each day.1

Swallow tablets whole; do not chew, crush, or split.1

Dosage

Available as neratinib maleate; dosage expressed in terms of neratinib.1

Adults

Breast Cancer
Extended Adjuvant Therapy of Early-stage Breast Cancer
Oral

240 mg once daily continuously for one year; initiate neratinib after completion of adjuvant trastuzumab therapy.1 2

Dosage Modification for Toxicity
Oral

Adverse effects may require temporary interruption and/or dosage reduction or permanent discontinuance.1 Adjust dosage based on individual safety and tolerability.1

If dosage reduction from 240 mg once daily is necessary, reduce dosage to 200 mg once daily.1

If adverse reactions recur with dosage of 200 mg once daily, reduce dosage to 160 mg once daily.1

If adverse reactions recur with dosage of 160 mg once daily, reduce dosage to 120 mg once daily.1

Dosages <120 mg once daily not recommended; discontinue drug if 120-mg daily dosage is not tolerated.1

Discontinue therapy in patients experiencing persistent adverse effects that do not recover to grade 0 or 1 or any toxicity that requires a treatment delay of >3 weeks.1

Grade 3 or 4 Toxicity
Oral

For grade 3 toxicity, temporarily interrupt therapy; upon recovery to grade 1 or less or to baseline within 3 weeks, resume therapy at reduced dosage.1

For grade 4 toxicity, permanently discontinue therapy.1

GI Toxicity
Oral

If diarrhea of any severity occurs in association with dehydration, pyrexia, hypotension, renal failure, or grade 3 or 4 neutropenia, temporarily interrupt neratinib therapy and initiate supportive measures (e.g., dietary modification, increased fluid intake); upon recovery to grade 1 or less or to baseline within 1 week of withholding the drug, resume therapy at the same dosage.1 If >1 week is required for recovery, resume therapy at reduced dosage.1 Administer loperamide hydrochloride 4 mg with subsequent doses of neratinib.1 If diarrhea recurs to grade 2 or greater severity at a reduced dosage of 120 mg once daily, permanently discontinue therapy.1

If grade 1 diarrhea (<4 stools per day over baseline) occurs, adjust antidiarrheal therapy and initiate supportive measures (e.g., dietary modification, increased fluid intake); upon recovery to baseline, administer loperamide hydrochloride 4 mg with each subsequent dose of neratinib.1

If grade 2 diarrhea (4–6 stools per day over baseline) lasting ≥5 days or grade 3 diarrhea (≥7 stools per day over baseline, fecal incontinence, requiring hospitalization, limiting self-care activities of daily living) lasting ≥2 days occurs, temporarily interrupt neratinib therapy and initiate supportive measures (e.g., dietary modification, increased fluid intake).1 Upon recovery to grade 1 or less or to baseline in <1 week of withholding the drug, resume therapy at the same dosage.1 If >1 week is required for recovery, resume therapy at reduced dosage.1 Administer loperamide hydrochloride 4 mg with subsequent doses of neratinib.1 If diarrhea recurs to grade 2 or greater severity at reduced dosage of 120 mg once daily, permanently discontinue therapy.1

If grade 2 diarrhea lasting <5 days or grade 3 diarrhea lasting <2 days occurs, adjust antidiarrheal therapy and initiate supportive measures (e.g., diet modification, increased fluid intake); upon recovery to grade 1 or less or to baseline, administer loperamide hydrochloride 4 mg with each subsequent dose of neratinib.1

If grade 4 diarrhea associated with life-threatening consequences or requiring urgent intervention occurs, permanently discontinue therapy.1

Hepatotoxicity
Oral

If grade 3 serum ALT (>5 to 20 times the ULN) or bilirubin (>3 to 10 times the ULN) elevations occur, temporarily interrupt therapy; upon recovery to grade 1 or less, resume therapy at reduced dosage.1 If grade 3 serum ALT or bilirubin elevations recur despite one dose reduction, permanently discontinue neratinib therapy.1

If grade 4 serum ALT (>20 times the ULN) or bilirubin (>10 times the ULN) elevations occur, permanently discontinue therapy.1

Prescribing Limits

Adults

Breast Cancer
Oral

Dosages <120 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.1

Severe preexisting hepatic impairment (Child-Pugh class C): Reduce initial dosage to 80 mg once daily.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Nerlynx

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Diarrhea

Severe diarrhea associated with dehydration, hypotension, and renal impairment reported; generally occurs during the first month of therapy.1 Median time to onset of grade 3 or greater diarrhea: 8 days.1 Median cumulative duration of grade 3 or greater diarrhea: 5 days.1

Antidiarrheal prophylaxis recommended with loperamide during initial 2 cycles of neratinib therapy.1 (See General under Dosage and Administration.) Monitor patients for development of diarrhea and, if necessary, treat with appropriate therapy (e.g., antidiarrheal agents, fluid replacement).1 Additional antidiarrheal agents may be necessary for loperamide-refractory diarrhea.1 Perform stool cultures as clinically indicated if grade 3 or 4 diarrhea or diarrhea of any severity associated with dehydration, pyrexia, or neutropenia occurs.1 In addition, evaluate liver function tests in patients experiencing grade 3 or greater diarrhea.1 (See Hepatic Toxicity under Cautions.)

If diarrhea occurs, temporary interruption, dosage reduction, or discontinuance of neratinib may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatic Toxicity

Elevations in ALT or AST concentrations reported.1

Monitor liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase concentrations) at baseline, monthly for first 3 months of therapy, every 3 months thereafter during therapy, and as clinically indicated.1 Evaluate ALT, AST, total and fractionated bilirubin, and alkaline phosphatase concentrations and prothrombin time in patients experiencing grade 3 or greater diarrhea requiring IV fluid replacement and those experiencing signs or symptoms of hepatotoxicity (e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, pyrexia, rash, eosinophilia).1 (See Diarrhea under Cautions.)

If grade 3 or 4 serum ALT or bilirubin elevations occur, temporary interruption followed by dosage reduction or discontinuance of neratinib may be necessary; also consider alternate causes of hepatotoxicity.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryofetal toxicity and teratogenicity demonstrated in animals.1 Effects on long-term memory observed in male pups when pregnant rats received the drug from day 7 of gestation through day 20 of lactation.1

Avoid pregnancy during therapy.1 Advise women of childbearing potential to use effective contraception while receiving neratinib and for ≥1 month after discontinuance of the drug.1 Advise men who are partners of such women to use effective contraceptive methods while receiving neratinib and for 3 months after the last dose.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether neratinib or its metabolites are distributed into human milk.1 Effects on nursing infants and milk production also unknown.1 Discontinue nursing during therapy and for ≥1 month after drug discontinuance.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Higher incidences of serious adverse reactions (e.g., vomiting, diarrhea, renal failure, dehydration) and discontinuance of neratinib due to adverse reactions observed in patients ≥65 years of age compared with younger adults.1

Hepatic Impairment

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): Peak plasma concentrations and systemic exposure not substantially altered.1 No dosage adjustment required.1

Severe preexisting hepatic impairment (Child-Pugh class C): Peak plasma concentrations and systemic exposure increased 273 and 281%, respectively.1 Dosage adjustment required.1 (See Special Populations under Dosage and Administration.)

Renal Impairment

Not studied in patients with renal impairment but neratinib is not extensively eliminated in urine.7 No dosage adjustment required.7

Common Adverse Effects

Diarrhea,1 2 nausea,1 2 abdominal pain,1 2 fatigue,1 2 vomiting,1 2 headache,2 rash,1 2 stomatitis,1 decreased appetite,1 2 muscle spasms,1 2 dizziness,2 dyspepsia.1

Interactions for Nerlynx

Neratinib is primarily metabolized by CYP3A4 and, to a lesser extent, by flavin-containing monooxygenase (FMO).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP3A4 inhibitors: Possible increased systemic exposure to neratinib and increased risk of adverse effects.1 5 Moderate CYP3A4 inhibitors not specifically studied in drug interaction studies with neratinib, but consider potential for clinically important pharmacokinetic interactions.1 Avoid concomitant use with potent or moderate CYP3A4 inhibitors.1 (See Specific Drugs and Foods under Interactions.)

Potent or moderate CYP3A4 inducers: Possible decreased systemic exposure to neratinib and its active N-desmethyl (M6) and dimethylamine N-oxide (M7) metabolites7 and reduced efficacy of neratinib.1 Moderate CYP3A4 inducers not specifically studied in drug interaction studies with neratinib, but consider potential for clinically important pharmacokinetic interactions.1 Avoid concomitant use with potent or moderate CYP3A4 inducers.1 (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased oral bioavailability and reduced efficacy of neratinib) with drugs that increase gastric pH.1 6 7

Substrates of P-Glycoprotein Transport Systems

Potential pharmacokinetic interaction (increased systemic exposure of substrates).1

Use with caution.1 Consider dosage reduction of substrates with a narrow therapeutic index.7

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antacids

Possible decreased bioavailability and reduced efficacy of neratinib1 6 7

Administer 3 hours prior to neratinib1

Anticonvulsants (e.g., carbamazepine, phenytoin)

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Ketoconazole: Increased peak concentrations and AUC of neratinib by 321 and 481%, respectively1 5

Avoid concomitant use1

Aprepitant

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Bosentan

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil)

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Ciprofloxacin

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Clotrimazole

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Cobicistat

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Conivaptan

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Crizotinib

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Cyclosporine

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Dabigatran

Possible increased systemic exposure to dabigatran1

Use with caution1

Digoxin

Increased peak plasma concentration and AUC of digoxin by 54 and 32%, respectively1

Consider digoxin dosage reduction; use with caution1

Dronedarone

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Elvitegravir

Ritonavir-boosted elvitegravir: Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Enzalutamide

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Fexofenadine

Possible increased systemic exposure to fexofenadine1

Use with caution1

Fluvoxamine

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Grapefruit or grapefruit juice

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

HCV antivirals (fixed combination of ombitasvir, paritaprevir, and ritonavir with or without dasabuvir)

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Histamine H2-receptor antagonists

Possible decreased neratinib bioavailability secondary to decreased solubility at higher pH1 6 7

Avoid concomitant use1

HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, etravirine)

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

HIV protease inhibitors (e.g., ritonavir-boosted indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir)

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Idelalisib

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Imatinib

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Macrolides (e.g., clarithromycin, erythromycin)

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Mitotane

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Modafinil

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Nefazodone

Possible increased systemic exposure to neratinib and increased adverse effects1 5

Avoid concomitant use1

Proton-pump inhibitors

Possible decreased neratinib bioavailability secondary to decreased solubility at higher pH1 6 7

Avoid concomitant use1

Rifampin

Decreased AUC of neratinib and its active metabolites (M6, M7) by 87 and 37–49%, respectively; peak plasma concentration of neratinib decreased by 76%1

Avoid concomitant use1

St. John’s wort (Hypericum perforatum)

Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy1

Avoid concomitant use1

Nerlynx Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations and AUC of neratinib and its major active metabolites (M3, M6, M7) attained in approximately 2–8 hours.1

Systemic exposure increases in a less than proportional manner following administration of neratinib 40–400 mg once daily;1 mean accumulation ratio is 1.14.10

Food

Administration with high-fat meal increased neratinib peak plasma concentrations and AUC by 1.7- and 2.2-fold, respectively.1

Administration with a standard breakfast increased neratinib peak plasma concentrations and AUC by 1.2- and 1.1-fold, respectively.1

Special Populations

Peak plasma concentrations and AUC increased 273 and 281%, respectively, in individuals with severe hepatic impairment (Child-Pugh class C).1 Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially affect systemic exposure.1

Pharmacokinetics not studied in renal impairment; however, neratinib is not extensively eliminated in urine.1

Age, gender, and race do not substantially affect pharmacokinetics.1 12

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

>99% (mainly albumin and α1-acid glycoprotein), independent of concentration.1

Elimination

Metabolism

Principally metabolized by CYP3A4 and, to a lesser extent, by FMO to active pyridine N-oxide (M3), N-desmethyl (M6), dimethylamine N-oxide (M7), and bis-N-oxide (M11) metabolites.1 7

Elimination Route

Eliminated in feces (approximately 97.1% of recovered dose) and urine (1.13%).1

Half-life

Neratinib: 14.6 hours.1

M3: 21.6 hours.1

M6: 13.8 hours.1

M7: 10.4 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Potent, selective, and irreversible inhibitor of HER2, HER4, and EGFR tyrosine kinases.1 8

  • Reduces phosphorylation of EGFR and HER2.8 9

  • Inhibits downstream signaling of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) pathways.1 8 9

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • If a dose is missed, importance of administering the next dose at the regularly scheduled time; do not administer an additional dose to make up for a missed dose.1

  • Risk of diarrhea.1 Importance of informing patients how to manage diarrhea (e.g., dietary modification, antidiarrheal agents) to maintain 1–2 bowel movements per day.1 Importance of informing clinician if severe diarrhea or diarrhea associated with weakness, dizziness, or fever occurs.1

  • Risk of hepatotoxicity.1 Importance of advising patients to immediately report possible signs and symptoms of hepatotoxicity (e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain, jaundice, fever, rash, pruritus) to their clinician.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use effective methods of contraception while receiving the drug and for ≥1 month after discontinuance of therapy.1 Advise men who are partners of such women to use effective methods of contraception while receiving the drug and for 3 months after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving neratinib and for ≥1 month after discontinuance of therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of neratinib is restricted.3 (See Restricted Distribution Program under Dosage and Administration.)

Neratinib Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

40 mg (of neratinib)

Nerlynx

Puma Biotechnology

AHFS DI Essentials™. © Copyright 2018, Selected Revisions September 10, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Puma Biotechnology, Inc. Nerlynx (neratinib) tablets prescribing information. Los Angeles, CA; 2017 Jul.

2. Chan A, Delaloge S, Holmes FA et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016; 17:367-77. http://www.ncbi.nlm.nih.gov/pubmed/26874901?dopt=AbstractPlus

3. Puma Biotechnology, Inc. Access and support: How to get Nerlynx. From the Nerlynx website. 2017 Oct. Accessed 2017 Nov 8. https://nerlynx.com/hcp/access-and-support/how-to-get-nerlynx

4. Abbas R, Hug BA, Leister C et al. A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol. 2012; 70:191-9. http://www.ncbi.nlm.nih.gov/pubmed/22418773?dopt=AbstractPlus

5. Abbas R, Hug BA, Leister C et al. Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects. Br J Clin Pharmacol. 2011; 71:522-7. http://www.ncbi.nlm.nih.gov/pubmed/21395644?dopt=AbstractPlus

6. Keyvanjah K, DiPrimeo D, Li A et al. Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects. Br J Clin Pharmacol. 2017; 83:554-561. http://www.ncbi.nlm.nih.gov/pubmed/27628584?dopt=AbstractPlus

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208051Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208051Orig1s000MultidisciplineR.pdf

8. Echavarria I, López-Tarruella S, Márquez-Rodas I et al. Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther. 2017; 17:669-679. http://www.ncbi.nlm.nih.gov/pubmed/28649882?dopt=AbstractPlus

9. Chan A. Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness. Ther Adv Med Oncol. 2016; 8:339-50. http://www.ncbi.nlm.nih.gov/pubmed/27583026?dopt=AbstractPlus

10. Kourie HR, Chaix M, Gombos A et al. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016; 12:947-57. http://www.ncbi.nlm.nih.gov/pubmed/27284682?dopt=AbstractPlus

11. Rabindran SK, Discafani CM, Rosfjord EC et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004; 64:3958-65. http://www.ncbi.nlm.nih.gov/pubmed/15173008?dopt=AbstractPlus

12. Ito Y, Suenaga M, Hatake K et al. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study. Jpn J Clin Oncol. 2012; 42:278-86. http://www.ncbi.nlm.nih.gov/pubmed/22371427?dopt=AbstractPlus

Hide