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

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

The objectives of this pivotal study are:

1. to evaluate bioavailability of an extended-release and immediate release Codeine Phosphate/Guaifenesin tablet at steady state following multiple oral administration
2. to assess the safety and tolerability of this Codeine Phosphate/Guaifenesin extended release formulation.

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.

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.