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Codeprex Pennkinetic (Codeine Polistirex / Chlorpheniramine Polistirex) - Description and Clinical Pharmacology


(codeine polistirex and chlorpheniramine polistirex)
Extended-Release Suspension


Codeprex Extended-Release Suspension is a pink to purple-pink colored, cherry-cream flavored suspension. Each teaspoonful (5 mL) of Codeprex Extended-Release Suspension contains codeine polistirex equivalent to 20 mg of codeine and chlorpheniramine polistirex equivalent to 4 mg of chlorpheniramine maleate and excipients. These excipients include: Citric acid (anhydrous), D&C Red No. 33, edetate disodium, ethylcellulose, flavor, glycerin, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium, polyethylene glycol 3350, polysorbate 80, propylparaben, propylene glycol, purified water, sodium hydroxide, sodium polystyrene sulfonate, sucrose, vegetable oil, and xanthan gum. Codeine is an opiate antitussive. Chlorpheniramine is an antihistamine. Codeprex is for oral use only.

Chemically, codeine is (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol. Its empirical formula is C18H21NO3, and its molecular weight is 299.36. Codeine polistirex is the sulfonated styrene-divinylbenzene copolymer complex with codeine. Its structural formula is:

Chemically, chlorpheniramine is γ-(4-chlorophenyl)- N,N -dimethyl-2-pyridinepropanamine. Its empirical formula is C16H19ClN2, and its molecular weight is 274.80 (free base). Chlorpheniramine polistirex is the sulfonated styrene-divinylbenzene copolymer complex with chlorpheniramine. Its structural formula is:




The precise mechanism of action of codeine and other opiates is not known but it is believed to act in the medulla with depression of the cough center and to a lesser degree the respiratory center.


Chlorpheniramine is a propylamine derivative antihistamine (H1-receptor antagonist) of the alkylamine class that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.


The bioavailability of Codeprex has been assessed in single- and multiple-dose crossover studies in healthy adults. In a single-dose study, pharmacokinetic parameters for Codeprex were evaluated in 20 fasting subjects and compared to two doses of an immediate-release reference solution containing 20 mg codeine and 4 mg chlorpheniramine maleate. In a separate study, single doses of Codeprex were administered to 36 subjects, under both fed and fasted conditions. In a multi-dose study, the steady state pharmacokinetic parameters of codeine and chlorpheniramine were compared in 26 subjects who received Codeprex administered twice daily and an immediate-release reference solution administered four times daily for one week.


In two single dose studies with Codeprex in fasting, healthy volunteers, codeine mean (S.D.) peak plasma concentrations were 53.8 (13.4) ng/mL and 61.7 (18.5) ng/mL. Chlorpheniramine mean (S.D.) peak plasma concentrations were 7.9 (1.6) ng/mL and 7.4 (1.6) ng/mL. Peak plasma codeine levels were reached approximately 2.5 to 3 hours following dosing. Peak plasma chlorpheniramine levels were reached approximately 6.5 to 7 hours following dosing. Peak plasma concentrations of codeine and chlorpheniramine were reached approximately 2.7 and 9 hours respectively after dosing with the immediate-release reference solution.

Following multiple dosing with Codeprex, codeine mean (S.D.) peak plasma concentrations of 100.5 (26.8) ng/mL were reached at approximately 2 hours. Chlorpheniramine mean (S.D.) peak concentrations of 35.8 (10.0) ng/mL were reached approximately 3 hours following multiple dosing. Peak plasma concentrations of codeine and chlorpheniramine were reached approximately 1 and 3 hours respectively after dosing with the immediate-release reference solution.


Codeine has been reported to have an apparent volume of distribution of approximately 3-6 L/kg, indicating extensive distribution of the drug into tissues. About 7-25% of codeine, reportedly, is bound to plasma proteins. Codeine passes the blood brain barrier and the placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast milk.

Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It reportedly has an apparent steady-state volume of distribution of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine and its metabolites likely cross the placental barrier and are excreted into human breast milk.

Food Effects

The bioavailability of Codeprex Extended-Release Suspension was not affected when administered after a high fat meal. In a two-way crossover study, pharmacokinetic parameters were evaluated in 36 healthy subjects and no differences between fed and fasted groups were observed for either Cmax or AUC for either codeine or chlorpheniramine. A statistically significant increase in Tmax for chlorpheniramine from 6.3 hours to 9.1 hours was observed after a high fat meal; however this increase is unlikely to be clinically important.


Codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide, and to a minor extent via O -demethylation to morphine (approximately 10% of administered dose) and via N -demethylation to norcodeine (approximately 10% of administered dose). Cytochrome P-450 2D6 is the major enzyme mediating O -demethylation of codeine to morphine. Norcodeine formation is predominately catalyzed by cytochrome P-450 3A4 mediated N -demethylation. Norcodeine and morphine are further metabolized by conjugation with glucuronic acid. These metabolites and their conjugates are pharmacologically active. Whether codeine-6-glucuronide has pharmacological activity is unknown, but activity similar to codeine itself is expected.

Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono- and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by cytochrome P-450 2D6.


Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine.

Plasma half-lives of codeine have been reported to be approximately 3 hours.

Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate.

Plasma half-lives for chlorpheniramine have been reported to range from approximately 2 to 43 hours in adults and 5 to 16 hours in children.

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