Triacin C

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, sodiumsaccharin、山梨糖醇、甘油、柠檬酸、柠檬酸钠、caramel flavor and USP purified water.

Triacin-C produces antitussive, antihistaminic andnasal decongestanteffects. 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

Triprolidine Hydrochloride, USP

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

Pseudoephedrine Hydrochloride, USP

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

INDICATIONS

Triacin-C is indicated for temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.

DOSAGE AND ADMINISTRATION

DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND RESPONSE OF THE PATIENT.

Usual Dose:	Teas poonfuls (5 mL)
Adults and children 12 years and older	2 teaspoonfuls (10 mL) every 4 to 6 hours, not to exceed 8 teaspoonfuls (40 mL) in 24 hours.
Children 6 to under 12 years	1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 4 teaspoonfuls (20 mL) in 24 hours.
Children 2 to under 6 years	½ teaspoonful (2.5 mL) every 4 to 6 hours, not to exceed 2 teaspoonfuls

HOW SUPPLIED

Triacin-C, is supplied in a colorless, caramel flavored vehicle in 16 fl oz pint (473 mL) size bottles.

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.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.].

Dispense in a tight, light-resistant container as defined in the USP.

Manufactured for: STI Pharma LLC Langhorne, PA 19047. Revised: Jul 2015

SIDE EFFECTS

(The most frequent adverse reactions are underlined.)

General:Dryness of mouth,dryness of nose,dryness of throat,urticaria, drug rash,anaphylactic shock,photosensitivity, excessiveperspirationand chills.

Cardiovascular System:Hypotension, headache,palpitations,tachycardia, extrasystoles.

Hematologic System:Hemolytic anemia,thrombocytopenia,agranulocytosis.

Nervous System:Sedation,sleepiness,dizziness,disturbed coordination, fatigue, confusion, restlessness, excitation, anxiety, nervousness,tremor, irritability, insomnia,euphoria, paresthesias, blurred vision,diplopia,vertigo,tinnitus, acutelabyrinthitis, hysteria, neuritis, convulsions, CNS depression,hallucination.

G.I. System:Epigastric distress,anorexia, nausea, vomiting, diarrhea, constipation.

G.U. System:Urinary frequency,difficult urination, urinary retention, early menses.

Respiratory System:Thickening of bronchial secretions, tightness of chest andwheezing,nasalstuffiness,respiratory depression.

DRUG INTERACTIONS

Triacin-C may enhance the effects of:

1. Monoamine oxidase (MAO) inhibitors;
2. othernarcoticanalgesics, alcohol, general anesthetics, tranquilizers,sedative-hypnotics, surgicalskeletal musclerelaxants, or other CNS depressants, by causing increased CNS depression.

This product may diminish theantihypertensiveeffects of guanethidine, bethanidine, methyldopa and reserpine.

警告

Deaths Related To Ultra-Rapid Metabolism Of Codeine To Morphine

Respiratory depression and death have occurred in children who received codeine in thepostoperativeperiod followingtonsillectomyand/oradenoidectomyand had evidence of being ultrarapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine (seePRECAUTIONS-Nursing Mothers).

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6genotype(gene duplications denoted as *1/*1xN or *1/*2xN). Theprevalenceof this CYP2D6phenotypevaries widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (seeOVERDOSE).

Children withobstructive sleep apneawho are treated with codeine for post-tonsillectomy and/or adenoidectomy pain 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 all pediatric patients undergoing tonsillectomy and/or adenoidectomy (seeCONTRAINDICATIONS).

When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

Triacin-C should be used with considerable caution in patients with increasedintraocular pressure(narrow angleglaucoma), stenosingpeptic ulcer, pyloroduodenal obstruction, symptomatic prostatichypertrophy,bladderneck obstruction,hypertension,diabetes mellitus, ischemicheart disease, and hyperthyroidism.

In the presence ofhead injuryor other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure.

Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

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,gallbladderdisease orgallstones, respiratory impairment, cardiac arrhythmias, history of bronchialasthma, prostatic hypertrophy or urethralstricture, and in patients known to be taking other antitussive, antihistamine ordecongestantmedications. Patients’ self-medication habits should be investigated to determine their use of such medications. Triacin-C is intended for short-term use only.

Drug/Laboratory Test Interactions

Codeine

Narcotic administration may increase serumamylaselevels.

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,mutagenesisor 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 ofteratogenicharm 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 skeletalossificationin 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. (警告–Death Related To Ultra-Rapid Metabolism Of Codeine To Morphine).

Pediatric Use

Respiratory depression and death have occurred in children with obstructive sleepapneawho 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-operativepain managementin these patients (警告-Death Related To Ultra-Rapid Metabolism Of Codeine To MorphineandCONTRAINDICATIONS)

As in adults, the combination of an antihistamine, sympathomimeticamine和可待因或可以引起轻微刺激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, (seeCONTRAINDICATIONSandOVERDOSEsections).

Use In Elderly (Approximately 60 Years Or Older):

The ingredients in Triacin-C are more likely to cause adverse reactions in elderly patients.

OVERDOSE

Since Triacin-C is comprised of three pharmacologically different compounds, it is difficult to predict the exact manifestation of symptoms in a given individual. Reaction to an overdosage of this product may vary from CNS depression to stimulation. A detailed description of symptoms which are likely to appear after ingestion of an excess of the individual components follows:

Overdosage with codeine can cause transient euphoria, drowsiness, dizziness, weariness, diminution of sensitivity, loss of sensation, vomiting, transient excitement in children, and occasionally in adult women,miosisprogressing to nonreactive pinpoint pupils, itching sometimes with skin rashes and urticaria and clammy skin with mottledcyanosis. In more severe cases,muscularrelaxation with depressed or absentsuperficialand deep reflexes and a positiveBabinski signmay appear. Marked slowing of therespiratory ratewith inadequate pulmonaryventilationand consequent cyanosis may occur. Terminal signs includeshock,pulmonary edema, hypostatic oraspiration pneumoniaand respiratory arrest, with death occurring within 6-12 hours following ingestion.

Overdoses ofantihistaminesmay cause hallucinations, convulsions, or possibly death, especially in infants and children. Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients.

Overdosage with triprolidine may produce reactions varying from depression to stimulation of theCentral Nervous System(CNS); the latter is particularly likely in children.Atropine-like signs and symptoms (dry mouth, fixed dilated pupils, flushing, tachycardia, hallucinations, convulsions, urinary retention, cardiac arrhythmias and coma) may occur.

Overdosage with pseudoephedrine can cause excessive CNS stimulation resulting in excitement, nervousness, anxiety, tremor, restlessness and insomnia. Other effects include tachycardia, hypertension, pallor,mydriasis,hyperglycemiaand urinary retention. Severe overdosage may causetachypnea或喘息,幻觉,抽搐, ordelirium, but in some individuals there may be CNS depression withsomnolence, stupor or respiratory depression. Arrhythmias (includingventricularfibrillation) may lead to hypotension andcirculatorycollapse. Severehypokalemiacan occur, probably due to compartmental shift rather than depletion ofpotassium. No organ damage or significant metabolic derangement is associated with pseudoephedrine overdosage.

The toxic plasma concentration of codeine is not known with certainty. Experimental production of mild to moderate CNS depression in healthy, nontolerant subjects occurs at plasma concentrations of 0.5- 1.9ìg/mL when codeine is given by intravenous infusion. The singlelethaladu剂可待因lts is estimated to be from 0.5 to 1.0gram. It is also estimated that 5 mg/kg could be fatal in children. The LD (single, oral dose) of triprolidine is 163 to 308 mg/kg in the mouse (depending upon strain) and 840 mg/kg in the rat.

Insufficient data are available to estimate the toxic and lethal doses of triprolidine in humans. No reports of acutepoisoningwith triprolidine have appeared.

The LD (single, oral dose) of pseudoephedrine is 726 mg/kg in the mouse, 2206 mg/kg in the rat and 1177 mg/kg in the rabbit. The toxic and lethal concentrations in human biologic fluids are not known. Excretion rates increase with urine acidification and decrease with alkalinization. Few reports of toxicity due to pseudoephedrine have been published and no case of fatal overdosage is known.

Therapy, if instituted within 4 hours of overdosage, is aimed at reducing further absorption of the drug. In the conscious patient, vomiting should be induced even though it may have occurred spontaneously. If vomiting cannot be induced,gastriclavage is indicated. Adequate precautions must be taken to protect againstaspiration, especially in infants and children. Charcoal slurry or other suitable agents should be instilled into the stomach after vomiting or lavage.Salinecathartics ormilk of magnesiamay be of additional benefit.

In theunconsciouspatient, the airway should be secured with a cuffedendotracheal tubebefore attempting to evacuate the gastric contents. Intensive supportive and nursing care is indicated, as for any comatose patient.

If breathing is significantly impaired, maintenance of an adequate airway and mechanical support ofrespirationis the most effective means of providing adequateoxygenation.

Hypotension is an early sign of impendingcardiovascularcollapse and should be treated vigorously. Do not use CNS stimulants. Convulsions should be controlled by careful administration of diazepam or short-acting barbiturate, repeated as necessary. Physostigmine may be also considered for use in controlling centrally mediated convulsions.

Ice packs and cooling sponge baths, not alcohol, can aid in reducing the fever commonly seen in children.

For codeine, continuous stimulation that arouses, but does not exhaust, the patient is useful in preventing coma. Continuous or intermittent oxygen therapy is usually indicated, whilenaloxoneis useful as a codeineantidote. Close nursing care isessential.

Saline cathartics, such as milk ofmagnesia, help to dilute the concentration of the drugs in the bowel by drawing water into the gut, thereby hastening drug elimination.

Adrenergic receptor blocking agents are antidotes to pseudoephedrine. In practice, the most useful is the beta-blocker propranolol, which is indicated when there are signs of cardiac toxicity.

There are no specific antidotes to triprolidine.Histamineshould not be given.

Pseudoephedrine and codeine are theoretically dialyzable, but the procedures have not been clinically established.

In severe cases of overdosage, it is essential to monitor both the heart (by electrocardiograph) and plasma electrolytes and to give intravenous potassium as indicated by these continuous controls. Vasopressors may be used to treat hypotension, and excessive CNS stimulation may be counteracted withparenteraldiazepam. Stimulants should not be used.

CONTRAINDICATIONS

Triacin-C is contraindicated under the following conditions:

Codeine sulfate is contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.

Use In Newborn Or Premature Infants

This drug should not be used in newborn or premature infants.

Use In Lower Respiratory Disease

Antihistamines should not be used to treat lower respiratory tract symptoms, including asthma.

Hypersensitivity To(1) codeine phosphate or other narcotics; (2) triprolidine hydrochloride or other antihistamines of similar chemical structure; or (3) sympathomimetic amines, including pseudoephedrine.

Sympathomimetic amines are contraindicated in patients with severe hypertension, severe coronary artery disease and in patients on monoamine oxidase (MAO) inhibitor therapy (seeDRUG INTERACTIONS).

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 thegastrointestinal 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,spleenand 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,lungsand 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 systemiccirculation. Thevasoconstrictionelicited at these sites results in the shrinkage of swollen tissues in the sinuses and nasal passages.

Pseudoephedrine is rapidly and almost completely absorbed from thegastrointestinaltract. 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 byurine pH智慧与酸化,增加和减少h 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 Ndemethylation, parahydroxylation and oxidative deamination.

PATIENT INFORMATION

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 ultrarapid 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 obstructivesleep apneamay 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 (警告–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.” (警告–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 orsinuscongestion. 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.