Single Dose Trial of Extended Release Combination Tablet Codeine and Guaifenesin

Study Overview
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Brief Summary
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The objectives of this study are (a) to determine if drug levels from a single dose of an extended-release Codeine/Guaifenesin tablet are similar to an immediate-release tablet given every four hours containing lower doses considered safe for over-the-counter use; (b) to evaluate if food affects the drug levels of this extended-release Codeine/Guaifenesin tablet after a single administration; and (c) to assess the safety and tolerability of the Codeine/Guaifenesin extended-release and immediate release tablet formulations.

Official Title
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An Open-Label, Single-Dose, Crossover Comparative Bioavailability and Pharmacokinetic Study of Codeine Phosphate/Guaifenesin Extended-Release Tablet With Immediate-Release Tablet

Conditions
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Cough

Intervention / Treatment
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* Drug: IR Tablet under Fasted conditions
* Drug: ER Tablet under Fed Conditions
* Drug: ER Tablet under Fasted Conditions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy non-smoking volunteers (Female volunteers on a stable contraceptive medication regimen (> 3 months) may continue during the course of the study but its use must be documented), 18 to 45 years of age, inclusive; Ethnic Group: Arab & Mediterranean. Race: Mixed skin (white & black skin people). Body Mass Index (BMI) between 18 and 32 kg/m2, inclusive; willing and able to comply with the appropriate instructions necessary to complete the study, and; Fully informed of the risks of entering the study and willing to provide written informed consent. Subject is available for the whole study period and gave written informed consent If female, must be practicing abstinence or using a medically acceptable form of contraception (e.g., intrauterine device, hormonal birth control [continuously used for at least 3 months before first dose], or double barrier method). For the purpose of this study, all females are considered to be of childbearing potential unless they have been post - menopausal, biologically sterile, or surgically sterile (i.e., hysterectomy, bilateral oophorectomy, or tubal ligation) for more than one (1) yearNormal Physical examination. Vital signs within normal ranges. All laboratory screening results within the normal range, or being assessed as clinically Non-significant by the attending physician. Normal Kidney and Liver functions test. Exclusion Criteria: Women of childbearing potential who don't use any contraceptive method, pregnant and/or lactating women. Ethnic Group (Non- Arab &/ or Non- Mediterranean) A significant abnormality in the pre-study physical examination that would place the volunteer at risk during participation in the trial; A clinical laboratory test value outside of the accepted reference range that is deemed by the Investigator to be clinically significant; Require prescription medication on a regular basis; A clinically significant illness during the 28 days prior to Period 1 dosing (as determined by the Investigator); History of serious illness that can impact fate of drugs History of gastrointestinal obstruction, constipation, inflammatory bowel disease, gallbladder disease, pancreas disorder over last 2 years, or recent (over last 3 years) gastrointestinal tract surgery, including gall bladder resection; Known history or presence of cardiac, pulmonary, endocrine, musculoskeletal, neurological, hematological or disease. Subjects with acute pulmonary insufficiency, respiratory depression, acute or chronic severe respiratory insufficiency or history of any of these History of head injury, seizures over last 4 years deemed by the Investigator to be clinically significant; Mental disease History of kidney disease or urination problem over last 2 years deemed by the Investigator to be clinically significant Subjects with renal and/or hepatic insufficiency should be excluded Presence of any significant physical or organ abnormality History of low blood pressure is deemed by the Investigator to be clinically significant; A positive Hepatitis B surface antigen, Hepatitis C antibody screen, or a reactive HIV antibody screen; Known or suspected hypersensitivities, allergies, or other contraindications to Codeine or a related opioid and/or Guaifenesin; History of severe allergy or allergic reactions to study drug or related drugs or heparin Known history or presence of food allergies, or any condition known to interfere with the absorption, distribution, metabolism or excretion of drugs Known or suspected history of drug abuse within lifetime as judged by the Investigator; History of alcohol abuse or excessive intake of alcohol within last 5 years as judged by the Investigator; Positive screen for drugs of abuse, alcohol, or cotinine (nicotine) at screening or on admission to the unit prior to administration of investigational products; Use of drugs that induce or inhibit the hepatic metabolizing cytochrome P450 2D6 enzymes, within 30 days prior to administration of study formulations. Examples of inducers include: piperidins, carbamazepine, dexamethasone, rifampin. Examples of inhibitors include: cimetidine, diphenhydramine, fluvastatine, methadone, and ranitidine; Use of prescription medications within 21 days and OTC medications (including vitamins or herbal products) within 7 days (excluding flu vaccination) prior to the first administration of the study medication without Sponsor approval; Intake of Alcohol, caffeine, or xanthine beverages 16 hrs before each study drug administration. Use of any investigational drug within 30 days prior to first dosing; Use of any tobacco-containing product within 6 months of first dosing; Donated more than 400 mL of blood within 4 weeks before first dosing; Participation in another bioequivalence study and/or Clinical trials within 80 days prior to the start of this study Period I Exhausting physical exercise in the last 48 hours (e.g. weight lifting) or any recent significant change in dietary or exercise habits. Abnormal vital signs Abnormal Kidney and Liver functions test. In the opinion of the Investigator, unlikely or unable to successfully complete the study; Volunteer is vegetarian. Vomiting, Diarrhea on admission.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ER Tablet under Fasted Conditions<br>Administration of a single dose of two ER Tablets, combination of Codeine/Guaifenesin 30gm/600mg, to subjects under fasted conditions. | Drug: ER Tablet under Fasted Conditions<br>* Administration of two Codeine Phosphate/Guaifenesin 30mg/600mg ER Tablets under fasted conditions.<br>* Other names: Codeine Phosphate/Guaifenesin 30mg/600mg ER Tablet;|
| Active Comparator: IR Tablet under Fasted conditions<br>IR Tablet combination tablet of Codeine/Guaifenesin 20mg/400mg administered under fasted conditions as a single tablet every 4 hours during a 12 hour study [three doses] | Drug: IR Tablet under Fasted conditions<br>* Administration of IR Tablets combination of Codeine Phosphate/Guaifenesin 20mg/400mg every 4 hours for 12 hours total.<br>* Other names: Codeine Phosphate/Guaifenesin 20mg/400mg;|
| Experimental: ER Tablet under Fed Conditions<br>Administration of a single dose of two ER Tablets, combination of Codeine/Guaifenesin 30gm/600mg, following a standard high-fat breakfast. | Drug: ER Tablet under Fed Conditions<br>* Administration of two ER Tablet combination of Codeine Phosphate/Guaifenesin 30mg/600mg<br>* Other names: Codeine Phosphate/Guaifenesin 30mg/600mg ER Tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Levels of Codeine and Guaifenesin | Blood samples drawn prior to dosing with tablets, then at 19 additional time points over the next 24 hours. | 20 samples over 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Collect adverse event data during the dosing and sampling intervals | 24 hours |