A Study of Acetaminophen/Naproxen Sodium Fixed Combination Tablets in Adolescents 12 to <17 Years of Age With Pain

Orthodontic Pain Clinical Trial

Official title:

An Open-label, Single-dose, Pharmacokinetic Study of Acetaminophen/Naproxen Sodium Fixed Combination Tablets in Adolescents 12 to <17 Years of Age With Orthodontic Pain

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05844995
• Other study ID #: CCSPAP005203
• Secondary ID: CCSPAP005203
• Status: Completed
• Phase: Phase 1
• Start date: September 13, 2023
• Est. completion date: February 14, 2024

Study information

• Verified date: March 2024
• Source: Johnson & Johnson Consumer and Personal Products Worldwide
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the population pharmacokinetics of acetaminophen and naproxen from a novel acetaminophen /naproxen sodium fixed combination tablet in adolescents 12 to less than (<) 17 years of age with post-procedure orthodontic pain and to describe the effect of subject-specific covariates, including age and body weight, on inter-subject variability in acetaminophen and naproxen pharmacokinetics in adolescents 12 to <17 years of age with post-procedure orthodontic pain.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: February 14, 2024
• Est. primary completion date: February 12, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 12 Years to 16 Years

Eligibility

Inclusion Criteria:

• A parent or a legal guardian of the participant has signed and dated the informed consent document and a written assent has been signed by the participant

• Has undergone an orthodontic procedure within 72 hours prior to dosing

• Is otherwise a healthy adolescent between the ages of 12 to less than (<) 17 years at baseline (dosing). Health is defined as the absence of clinically relevant abnormalities as judged by the principle investigator (PI) on the basis of a detailed medical history, physical examination, blood pressure, respiratory rate and pulse rate measurements, and clinical laboratory tests. The responsible PI may request additional investigations or analyses if necessary

• Has a minimum weight of 72 pounds and has a Body Mass Index (BMI) between the 5th and 95th percentile for their age at dosing

• Has been fasted for at least 10 hours prior to dose administration of the investigational product

• Is a non-tobacco user or previous user who completely stopped smoking or using any form of tobacco or nicotine-containing product [including e-cigarettes, cigarettes, non-combusted cigarettes, cigars, smokeless tobacco (such as dip, snuff, snus, and chewing tobacco)] for at least 12 months before screening visit of this study

• If female, have a negative test for pregnancy at screening and baseline (dosing)

• Females of childbearing potential and males agree to the contraceptive requirements

• Is able to comprehend the requirements of the study (based upon clinical site personnel's assessment) and is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures specified within the protocol

• Are willing for investigational product of this study to be the only analgesic product used during the study

Exclusion Criteria:

• Use of prescription or non-prescription medications within a period less than 5 half-lives before the first investigational product (IP) administration unless these are contraceptives or occasional use of other medications approved by the Investigator

• Use of Ibuprofen within 6 hours prior to the dose administration of the investigational product

• Use of any vitamins, dietary and herbal supplements within seven days before first dose of study drug

• Has hypersensitivity to acetaminophen, naproxen, other non-steroidal anti-inflammatory drug (NSAIDs), including acetylsalicylic acid, or to any of the ingredients

• If female, has a positive pregnancy test or is breast-feeding or currently trying to become pregnant

• Has a positive test for human immunodeficiency virus (HIV) 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (anti-HCV)

• Has a positive test for drugs of abuse at screening or baseline (dosing)

• Has difficult venipuncture access and/or refuses to undergo venipuncture

• Has clinically significant renal or hepatic impairment according to the medically qualified Investigator discretion, or presence of a disease, which in the opinion of the Investigator, would preclude the use of IP

• Has a history of peptic ulcers, gastrointestinal bleeding of any etiology, bleeding disorders, gastrointestinal disease (including chronic heartburn or gastroesophageal reflux disease, or any other active inflammatory disease of the gastrointestinal tract such as ulcerative colitis or crohn's disease), or has a history of gastrointestinal surgery (including cholecystectomy) that would affect the pharmacokinetic (PK) assessment of the drug or the safety of the participant

• Has history of substance abuse, as judged by the PI, within 12 months preceding this study

• Has used alcohol within 24 hours of baseline visit and/or has positive alcohol test in expired air at screening or baseline visit

• Has used food or beverages containing xanthines (that is, tea, coffee, cola drinks, energy drinks or chocolate) for 48 hours prior to the dosing and during the study period

• Has used grapefruit and savoy oranges for 48 hours prior to the dosing and during the study period

• Participating in a clinical trial and/or treated with any investigational product within 3 months preceding the dose of study drug

• Has preplanned surgery, procedures, or personal commitments that would interfere with the conduct of the study

• Had an acute blood loss of 50 milliliter (mL) to 249 mL within the 30 days, or 250 mL to 449 mL within the 45 days, or greater than or equal to (>=) 450 mL within the 60 days before first dose administration

• Has any acute or chronic medical or psychiatric condition(s) that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the medically qualified Investigator, would make the participant inappropriate for entry into this study

• Has any clinically important abnormal value for serum chemistry, hematology, or urinalysis at screening. Laboratory values will generally be within the normal ranges, although minor deviations in tests (except those explicitly specified in the inclusion criteria) that are not considered clinically important by the Investigator are acceptable

• Is related to persons involved directly or indirectly with the conduct of the study (that is, principal investigator, sub-investigators, study coordinators, other study personnel, employees or contractors of the Sponsor or Johnson & Johnson (J&J) subsidiaries, and the family of each)

Related Conditions & MeSH terms

• Orthodontic Pain

Intervention

Drug:
• Acetaminophen/Naproxen Sodium
Fixed dose combination of acetaminophen/naproxen sodium tablet will be administered orally.

Locations

Country	Name	City	State
United States	JBR Clinical Research LLP	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Johnson & Johnson Consumer Inc. (J&JCI)

Country where clinical trial is conducted

United States, 

References & Publications (47)

Altman RD. A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain. Clin Exp Rheumatol. 2004 Jan-Feb;22(1):110-7. — View Citation

Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006 Jan;79(1):9-19. doi: 10.1016/j.clpt.2005.09.009. No abstract available. — View Citation

Bernhardt MK, Southard KA, Batterson KD, Logan HL, Baker KA, Jakobsen JR. The effect of preemptive and/or postoperative ibuprofen therapy for orthodontic pain. Am J Orthod Dentofacial Orthop. 2001 Jul;120(1):20-7. doi: 10.1067/mod.2001.115616. — View Citation

Cheng C, Xie T, Wang J. The efficacy of analgesics in controlling orthodontic pain: a systematic review and meta-analysis. BMC Oral Health. 2020 Sep 18;20(1):259. doi: 10.1186/s12903-020-01245-w. — View Citation

Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet. 1997 Apr;32(4):268-93. doi: 10.2165/00003088-199732040-00002. — View Citation

Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982 Mar-Apr;7(2):93-107. doi: 10.2165/00003088-198207020-00001. — View Citation

Gritsiuk AI. [On the problem of the effect of prednisolone and salicylates on the fibrinolytic activity of the blood in patients with rheumatism]. Ter Arkh. 1967 Sep;39(9):60-1. No abstract available. Russian. — View Citation

Grosser T, Smyth E, FitzGerald. Anti-Inflammatory, Antipyretic, and Analgesic Agents; Pharmacotherapy of Gout. In: Goodman LS, Brunton LL, Chabner B, Knollman BC. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York, McGraw-Hill. 2011:959- 1004.

GUZMAN F, BRAUN C, LIM RK, POTTER GD, RODGERS DW. NARCOTIC AND NON-NARCOTIC ANALGESICS WHICH BLOCK VISCERAL PAIN EVOKED BY INTRA-ARTERIAL INJECTION OF BRADYKININ AND OTHER ALGESIC AGENTS. Arch Int Pharmacodyn Ther. 1964 Jun 1;149:571-88. No abstract available. — View Citation

Harrington JT, Isner JM, Kassirer JP. Our national obsession with potassium. Am J Med. 1982 Aug;73(2):155-9. doi: 10.1016/0002-9343(82)90171-1. No abstract available. — View Citation

Inc., P., PRODUCT MONOGRAPH, PEDIAPHARM NAPROXEN SUSPENSION, naproxen, 25 mg/mL Suspension, USP, Non-Steroidal Anti-Inflammatory Drug (NSAID) 2018.

Ji P, Wang Y, Li Z, Doddapaneni S, Hertz S, Furness S, Sahajwalla CG. Regulatory review of acetaminophen clinical pharmacology in young pediatric patients. J Pharm Sci. 2012 Dec;101(12):4383-9. doi: 10.1002/jps.23331. Epub 2012 Oct 16. — View Citation

Krishnan V. Orthodontic pain: from causes to management--a review. Eur J Orthod. 2007 Apr;29(2):170-9. doi: 10.1093/ejo/cjl081. — View Citation

Levy G. Comparative pharmacokinetics of aspirin and acetaminophen. Arch Intern Med. 1981 Feb 23;141(3 Spec No):279-81. doi: 10.1001/archinte.141.3.279. — View Citation

LIM RK, GUZMAN F, RODGERS DW, GOTO K, BRAUN C, DICKERSON GD, ENGLE RJ. SITE OF ACTION OF NARCOTIC AND NON-NARCOTIC ANALGESICS DETERMINED BY BLOCKING BRADYKININ-EVOKED VISCERAL PAIN. Arch Int Pharmacodyn Ther. 1964 Nov 1;152:25-58. No abstract available. — View Citation

Liu DJ, Collaku A, Youngberg SP. Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation. Int J Clin Pharmacol Ther. 2015 Feb;53(2):172-81. doi: 10.5414/CP202146. — View Citation

Mallet C, Daulhac L, Bonnefont J, Ledent C, Etienne M, Chapuy E, Libert F, Eschalier A. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 2008 Sep 30;139(1):190-200. doi: 10.1016/j.pain.2008.03.030. Epub 2008 May 15. — View Citation

McGilveray IJ, Mattok GL, Fooks JR, et al. Acetaminophen II: A comparison of the physiological availabilities of different commercial dosage forms. Can J Pharmaceut Sci 1971;6:38-42.

McNeil Consumer & Specialty Pharmaceuticals Clinical Pharmacology Report for Protocol 02- 161: Tolerability and multiple-dose pharmacokinetics of acetaminophen (paracetamol) at and above the currently recommended dose. Fort Washington, PA. McNeil Consumer & Specialty Pharmaceuticals Company. Aug 2005.

McNeil Consumer Products Company Data Listings for Protocol 1-224: A double-blind study of the comparative antipyretic effectiveness and safety of a single 10 mg/kg, 20 mg/kg or 30 mg/kg dose of acetaminophen. Sep 1981. [Meta-Analysis Code P81224]

McNeil Consumer Products Company Report for Protocol 93-308: Pharmacokinetic and pharmacodynamic modeling of acetaminophen in febrile children: Evaluation of three products. Fort Washington, PA. McNeil Consumer Products Company. 1994. [Meta-Analysis Code P93308]

McNeil Consumer Products Company Statistical Report 65 for Protocol 0-220: A double-blind multiple-dose study of the comparative antipyretic effectiveness and safety of standard and double standard doses of acetaminophen in febrile children. Fort Washington, PA. McNeil Consumer Products Company. Jun 1986. [Meta-Analysis Code P80220]

McNeil Consumer Products Company Statistical Report 7: Interim statistical analysis of the study of the bioavailability and antipyretic effectiveness of acetaminophen in children. Fort Washington, PA. McNeil Consumer Products Company. Dec 1978. [Meta-Analysis Code P00102]

McNeil Protocol 2-227 Data Listings. A double-blind study of the comparative antipyretic effectiveness and safety of a single 15 mg/kg, 30 mg/kg or 40 mg/kg dose of acetaminophen. Oct 1982 [Meta-Analysis Code P82227]

Mehlisch DR, Aspley S, Daniels SE, Southerden KA, Christensen KS. A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study. Clin Ther. 2010 Jun;32(6):1033-49. doi: 10.1016/j.clinthera.2010.06.002. — View Citation

Milligan TP, Morris HC, Hammond PM, Price CP. Studies on paracetamol binding to serum proteins. Ann Clin Biochem. 1994 Sep;31 ( Pt 5):492-6. doi: 10.1177/000456329403100512. — View Citation

Monk AB, Harrison JE, Worthington HV, Teague A. Pharmacological interventions for pain relief during orthodontic treatment. Cochrane Database Syst Rev. 2017 Nov 28;11(11):CD003976. doi: 10.1002/14651858.CD003976.pub2. — View Citation

Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg. 2010 Apr 1;110(4):1170-9. doi: 10.1213/ANE.0b013e3181cf9281. Epub 2010 Feb 8. — View Citation

Palma-Aguirre JA, Villalpando-Hernandez J, Novoa-Heckel G, Oliva I, Carino L, Lopez-Bojorquez E, Burke-Fraga V, Namur S, Gonzalez-de la Parra M. Bioavailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol (acetaminophen): single-dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects. Clin Ther. 2009 Feb;31(2):399-410. doi: 10.1016/j.clinthera.2009.02.002. — View Citation

Paracetamol In: Dollery C., editor. Therapeutic drugs. 2nd ed. Vol 2. Edinburgh: Churchill Livingstone. 1999

Paracetamol. In: Sweetman S, ed. Martindale - The Complete Drug Reference. London, UK: The Pharmaceutical Press. 37th ed. 2011:76-79.

Peterson RG, Rumack BH. Pharmacokinetics of acetaminophen in children. Pediatrics. 1978 Nov;62(5 Pt 2 Suppl):877-9. — View Citation

Pickering G, Loriot MA, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006 Apr;79(4):371-8. doi: 10.1016/j.clpt.2005.12.307. — View Citation

Polat O, Karaman AI, Durmus E. Effects of preoperative ibuprofen and naproxen sodium on orthodontic pain. Angle Orthod. 2005 Sep;75(5):791-6. doi: 10.1043/0003-3219(2005)75[791:EOPIAN]2.0.CO;2. Erratum In: Angle Orthod. 2008 Nov;78(6):976. Angle Orthod. 2008 Sep;78(5):798. — View Citation

Product Monograph for Aleve (Naproxen Sodium Tablets USP/Liquid Gels/Capsules 220 mg). Bayer Inc. Consumer Care. Revised January 8th, 2015.

Segre EJ. Naproxen sodium (Anaprox): pharmacology, pharmacokinetics and drug interactions. J Reprod Med. 1980 Oct;25(4 Suppl):222-5. — View Citation

Setiawati S et al. Bioequivalence study with two naproxen sodium tablet formulations in healthy subjects. J Bioequival Availab 2009;1: 28-33.

Sevelius H, Runkel R, Segre E, Bloomfield SS. Bioavailability of naproxen sodium and its relationship to clinical analgesic effects. Br J Clin Pharmacol. 1980 Sep;10(3):259-63. doi: 10.1111/j.1365-2125.1980.tb01753.x. — View Citation

Todd PA, Clissold SP. Naproxen. A reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states. Drugs. 1990 Jul;40(1):91-137. doi: 10.2165/00003495-199040010-00006. — View Citation

Topolski F, Moro A, Correr GM, Schimim SC. Optimal management of orthodontic pain. J Pain Res. 2018 Mar 16;11:589-598. doi: 10.2147/JPR.S127945. eCollection 2018. — View Citation

U.S. Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research (CDER). General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products. Guidance for Industry (Draft). (September 2022). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-clinical-pharmacologyconsiderations- pediatric-studies-drugs-including-biological-products

U.S. Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER). Population Pharmacokinetics, Guidance for Industry. (February 2022). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/population-pharmacokinetics

Valitalo P, Kumpulainen E, Manner M, Kokki M, Lehtonen M, Hooker AC, Ranta VP, Kokki H. Plasma and cerebrospinal fluid pharmacokinetics of naproxen in children. J Clin Pharmacol. 2012 Oct;52(10):1516-26. doi: 10.1177/0091270011418658. Epub 2011 Nov 8. — View Citation

Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012 Oct;52(10):1601-6. doi: 10.1177/0091270011422812. Epub 2011 Dec 12. No abstract available. — View Citation

Wilson JT, Brown RD, Bocchini JA Jr, Kearns GL. Efficacy, disposition and pharmacodynamics of aspirin, acetaminophen and choline salicylate in young febrile children. Ther Drug Monit. 1982;4(2):147-80. doi: 10.1097/00007691-198206000-00003. No abstract available. — View Citation

World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available. — View Citation

Zarif Najafi H, Oshagh M, Salehi P, Babanouri N, Torkan S. Comparison of the effects of preemptive acetaminophen, ibuprofen, and meloxicam on pain after separator placement: a randomized clinical trial. Prog Orthod. 2015;16:34. doi: 10.1186/s40510-015-0104-y. Epub 2015 Oct 14. — View Citation

* Note: There are 47 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Apparent Clearance (CL/F) of Acetaminophen/Naproxen Sodium	CL/F is defined as apparent clearance of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Apparent Central Volume of Distribution (Vc/F) After Oral Dosing of Acetaminophen/Naproxen Sodium	Vc/F is defined as apparent central volume of distribution after oral dosing of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Apparent Peripheral Volume of Distribution (Vp/F) After Oral Dosing of Acetaminophen/Naproxen Sodium	Vp/F is defined as apparent peripheral volume of distribution after oral dosing of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Apparent Inter-compartmental Clearance (Q/F) of Acetaminophen/Naproxen Sodium	Q/F is defined as apparent inter-compartmental clearance of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	First-order Absorption Rate Constant (Ka) of Acetaminophen/Naproxen Sodium	Ka is defined as first-order absorption rate constant of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Maximum Plasma Concentration (Cmax) of Acetaminophen/Naproxen Sodium	Cmax is defined as maximum plasma concentration of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Time of occurrence of Maximum Plasma Concentration (Tmax) of Acetaminophen/Naproxen Sodium	Tmax is defined as time of occurrence of maximum plasma concentration of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Area Under the Plasma Concentration versus Time Curve from Start of Drug Administration Until the Time of the Last Measurable Plasma Concentration (AUC[0-t])	AUC(0-t) is defined as area under the plasma concentration versus time curve from start of drug administration until the time of the last measurable plasma concentration of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Area Under the Plasma Concentration versus Time Curve From Start of Drug Administration Until Infinity (AUC[0-infinite])	AUC(0-infinite) is defined as area under the plasma concentration versus time curve from start of drug administration until infinity of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Terminal Elimination Rate Constant (lambda[z]) of Acetaminophen/Naproxen Sodium	Lambda(z) is defined as terminal elimination rate constant of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Primary	Half Life (t1/2) of Acetaminophen/Naproxen Sodium	T1/2 is defined as half life of acetaminophen/naproxen sodium.	Pre-dose up to 48 hours post dose
Secondary	Number of Participants with Adverse Events (AEs)	An AE is any untoward medical occurrence that occurs in participants after they have signed an informed consent for the study. The event does not need to have a suspected causal relationship with the investigational product (IP).	Up to 3 days