Codeine Phosphate/Guaifenesin ER Tablet 30 mg/600 mg Steady State Clinical Study

Study Overview
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Brief Summary
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The objectives of this pivotal study are: to evaluate bioavailability of an extended-release and immediate release Codeine Phosphate/Guaifenesin tablet at steady state following multiple oral administration to assess the safety and tolerability of this Codeine Phosphate/Guaifenesin extended release formulation.

Detailed Description
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This study will be a single-center, Two-site open-label, randomized, multiple-dose, two-treatment, two-period crossover design. During the course of the study, thirty eight (38) healthy adult volunteers will receive multiple doses of Codeine Phosphate/ Guaifenesin extended-release tablet 30 mg/600 mg and multiple doses of an IR Codeine Phosphate/ Guaifenesin immediate-release tablet 20 mg/400 mg tablet in two separate treatment periods. Volunteers will enter the clinic the day prior [approximately 12 hours] to each dosing and will be confined in the clinic for 7 nights for each treatment period. The extended release tablet (test) will be administered as two tablets two times a day, 12 hours apart, and the immediate release tablet (reference) will be administered as one tablet six times a day, 4 hours apart. Pre-dose blood samples will be collected prior to morning dose on Days 1, 2, 3, 4, 5, 6 and 7. On Day 7, Two extended release tablets will be given once in the morning and the immediate release tablet will be given three times, in the morning and 4 and 8 hours later. Serial blood samples will be collected on Day 7 for up to 12 hours post morning dose. On Day 7 volunteers will be released from the study site after the 12-hour blood collection if clinically appropriate and will return to the study site to start the next treatment after a minimum of 7 days of wash-out period, which begins the morning after the last dose taken of the previous Period.

Official Title
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An Open-Label, Randomized, Multiple-Dose, 2-Way Crossover Comparative Bioavailability Steady State Study of Codeine Phosphate/Guaifenesin Extended-Release Tablet in Healthy Subjects

Conditions
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Cough

Intervention / Treatment
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* Drug: Codeine Phosphate/Guaifenesin ER Tablet
* Drug: Codeine Phosphate/Guaifenesin IR Tablet


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 (minimum of 50 kg weight); 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) year Normal 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 48 before each study drug administration, and caffeine, or xanthine beverages 24 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Codeine Phosphate/Guaifenesin ER Tablet<br>Patients receiving an extended release tablet dosage form of a combination drug of Codeine Phosphate and Guaifenesin twice a day for 6 and a half days total. Total dosage [2 tablets] is 60 mg Codeine Phosphate and 1200 mg Guaifenesin twice a day for a daily total of 120 mg Codeine Phosphate and 2400 mg Guaifenesin. | Drug: Codeine Phosphate/Guaifenesin ER Tablet<br>* Provide two Codeine Phosphate and Guaifenesin ER Tablet every 12 hours for 6 1/2 days.<br>* Other names: Lot 100171;|
| Active Comparator: Codeine Phosphate/Guaifenesin IR Tablet<br>Patients receiving an immediate release tablet dosage form of a combination drug of Codeine Phosphate and Guaifenesin six times a day for 6 and a half days total. Dosage is 20 mg Codeine Phosphate and 400 mg Guaifenesin six times a day for a daily total of 120 mg Codeine Phosphate and 2400 mg Guaifenesin. | Drug: Codeine Phosphate/Guaifenesin IR Tablet<br>* Provide one Codeine Phosphate and Guaifenesin IR Tablet every 4 hours for 6 1/2 days<br>* Other names: Lot 100168;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) | Determination peak plasma concentration of each active ingredient during 12 hours following six days of dosing | One week | 
| Area under the plasma concentration versus time curve (AUC) | Determination of total area under the plasma concentration versus time curve (AUC) during the 12 hours following 6 days of dosing. | One week |