Triacin-C

TRIACIN-C- triprolidine hydrochloride, pseudoephedrine hydrochloride and codeine phosphate syrup
STI Pharma LLC

WARNING: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism (see WARNINGS — Codeine Phosphate — Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).

CV

DESCRIPTION

Each 5 mL (one teaspoonful) of syrup for oral administration contains:

Codeine Phosphate……10 mg

WARNING: May be habit forming.

Triprolidine Hydrochloride……1.25 mg

Pseudoephedrine Hydrochloride……30 mg

Alcohol 4.3%.

Inactive ingredients: sodium benzoate, methylparaben, sodium saccharin, sorbitol, glycerin, citric acid, sodium citrate, caramel flavor and USP purified water.

Triacin-C produces antitussive, antihistaminic and nasal decongestant effects. The components have the following chemical names and structural formulas:

Codeine Phosphate, USP

7,8-didehydro-4,5 α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate

Codeine
(click image for full-size original)

Triprolidine Hydrochloride, USP

(E)-2-[3(1-Pyrrolidinyl)-1-p-tolylpropenyl]pyridine monohydrochloride monohydrate

Triprolidine
(click image for full-size original)

Pseudoephedrine Hydrochloride, USP

Benzenemethanol, α-[1-(methylamino)ethyl]-,[S-(R*, R*)]- hydrochloride

Pseudo

CLINICAL PHARMACOLOGY

Codeine: Codeine probably exerts its antitussive activity by depressing the medullary (brain) cough center, thereby raising its threshold for incoming cough impulses.

Codeine is readily absorbed from the gastrointestinal tract, with a therapeutic dose reaching peak antitussive effectiveness in about 2 hours and persisting for 4 to 6 hours. Codeine is rapidly distributed from blood to body tissues and taken up preferentially by parenchymatous organs such as liver, spleen and kidney. It passes the blood brain barrier and is found in fetal tissue and breast milk.

The drug is not bound by plasma proteins nor is it accumulated in body tissues. Codeine is metabolized in the liver to morphine and norcodeine, each representing about 10 percent of the administered codeine dose. About 90 percent of the dose is excreted within 24 hours, primarily through the kidneys. Urinary excretion products are free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (under 4%) and hydrocodone (<1%). The remainder of the dose appears in the feces.

Triprolidine: Antihistamines such as triprolidine hydrochloride act as antagonists of the H1 histamine receptor. Consequently, they prevent histamine from eliciting typical immediate hypersensitivity responses in the nose, eyes, lungs and skin.

Animal distribution studies have shown localization of triprolidine in lung, spleen and kidney tissue. Liver microsome studies have revealed the presence of several metabolites with an oxidized product of the toluene methyl group predominating.

Pseudoephedrine: Pseudoephedrine acts as an indirect sympathomimetic agent by stimulating sympathetic (adrenergic) nerve endings to release norepinephrine. Norepinephrine in turn stimulates alpha and beta receptors throughout the body. The action of pseudoephedrine hydrochloride is apparently more specific for the blood vessels of the upper respiratory tract and less specific for the blood vessels of the systemic circulation. The vasoconstriction elicited at these sites results in the shrinkage of swollen tissues in the sinuses and nasal passages.

Pseudoephedrine is rapidly and almost completely absorbed from the gastrointestinal tract. Considerable variation in half-life has been observed (from about 4½ to 10 hours), which is attributed to individual differences in absorption and excretion. Excretion rates are also altered by urine pH, increasing with acidification and decreasing with alkalinization. As a result, mean half-life falls to about 4 hours at pH 5 and increases to 12 to 13 hours at pH 8.

After administration of a 60 mg tablet, 87 to 96% of the pseudoephedrine is cleared from the body within 24 hours. The drug is distributed to body tissues and fluids, including fetal tissue, breast milk and the central nervous system (CNS). About 55 to 75% of an administered dose is excreted unchanged in the urine; the remainder is apparently metabolized in the liver to inactive compounds by N-demethylation, parahydroxylation and oxidative deamination.

PRECAUTIONS

General: Triacin-C should be prescribed with caution for certain special-risk patients, such as the elderly or debilitated, and for those with severe impairment of renal or hepatic function, gallbladder disease or gallstones, respiratory impairment, cardiac arrhythmias, history of bronchial asthma, prostatic hypertrophy or urethral stricture, and in patients known to be taking other antitussive, antihistamine or decongestant medications. Patients’ self-medication habits should be investigated to determine their use of such medications. Triacin-C is intended for short-term use only.

Information For Patients:
Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. As a result, codeine is contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression (see WARNINGS – Death Related to Ultra-Rapid metabolism of Codeine to Morphine).
1. Patients should be warned about engaging in activities requiring mental alertness such as driving a car, operating dangerous machinery or hazardous appliances.
2. Patients with a history of glaucoma, peptic ulcer, urinary retention or pregnancy should be cautioned before starting this product.
3. Patients should be told not to take alcohol, sleeping pills, sedatives or tranquilizers while taking Triacin-C.
4. Antihistamines may cause dizziness, drowsiness, dry mouth, blurred vision, weakness, nausea, headache or nervousness in some patients.
5. Patients should be told to store this medicine in a tightly closed container in a dry, cool place away from heat or direct sunlight and out of the reach of children.
6. Nursing Mothers – refer to following section titled “Nursing Mothers.” (see WARNINGS – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).

This product should not be used by persons intolerant to sympathomimetics used for the relief of nasal or sinus congestion. Such drugs include ephedrine, epinephrine, phenylephrine and phenylpropanolamine. Symptoms of intolerance include drowsiness, dizziness, weakness, difficulty in breathing, tenseness, muscle tremors or palpitations.

Codeine may be habit-forming when used over long periods or in high doses. Patients should take the drug only for as long, in the amounts, and as frequently as prescribed.

Drug Interactions: Triacin-C may enhance the effects of:

1. Monoamine oxidase (MAO) inhibitors;
2. other narcotic analgesics, alcohol, general anesthetics, tranquilizers, sedative-hypnotics, surgical skeletal muscle relaxants, or other CNS depressants, by causing increased CNS depression.

This product may diminish the antihypertensive effects of guanethidine, bethanidine, methyldopa and reserpine.

Drug/Laboratory Test Interactions: Codeine: Narcotic administration may increase serum amylase levels.

Carcinogenesis, Mutagenesis, Impairment Of Fertility: No adequate studies have been conducted in animals to determine whether the components of Triacin-C have a potential for carcinogenesis, mutagenesis or impairment of fertility.

Pregnancy: Teratogenic Effects – Pregnancy category C. Animal reproduction studies have not been conducted with Triacin-C. It is also not known whether this product can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. This product should be given to a pregnant woman only if clearly needed.

Teratology studies have been conducted with the three ingredients of Triacin-C. Pseudoephedrine studies were conducted in rats at doses up to 150 times the human dose; triprolidine was studied in rats and rabbits at doses up to 125 times the human dose, and codeine studies were conducted in rats and rabbits at doses up to 150 times the human dose. No evidence of teratogenic harm to the fetus was revealed in any of these studies. However, overt signs of toxicity were observed in the dams which received pseudoephedrine. This was reflected in reduced average weight and length and rate of skeletal ossification in their fetuses.

Nursing Mothers: The components of Triacin-C are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from maternal ingestion of this product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (see WARNINGS – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).

Pediatric Use: Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients (see WARNINGS — Death Related to Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS)

As in adults, the combination of an antihistamine, sympathomimetic amine and codeine can elicit either mild stimulation or mild sedation in pediatric patients. In pediatric patients particularly, the ingredients in this drug product in overdosage may produce hallucinations, convulsions and death. Symptoms of toxicity in pediatric patients may include fixed dilated pupils, flushed face, dry mouth, fever, excitation, hallucinations, ataxia, incoordination, athetosis, tonic clonic convulsions and postictal depression, (see CONTRAINDICATIONS and OVERDOSAGE sections).

Use In Elderly (Approximately 60 Years Or Older): The ingredients in Triacin-C are more likely to cause adverse reactions in elderly patients.

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