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phenylephrine hydrochloride and
codeine phosphate liquid
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Each 5 mL (1 teaspoonful) of cotton candy flavored liquid for oral administration contains:
Brompheniramine Maleate is an antihistamine having the chemical name, 2-Pyridinepropanamine,γ-(4-bromophenyl)-N, N-dimethyl-, (±)-,(Z)-2-butenedioate (1:1). Its structure is as follows:
C16H19BrN2•C4H4O4 M.W. 435.31
Phenylephrine Hydrochloride is an orally effective nasal decongestant having the chemical name, (–)-m-Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride, an adrenergic which occurs as white or practically white, odorless crystals, having a bitter taste. It is freely soluble in water and in alcohol. Its structure is as follows:
C9H13NO2 • HCl M.W. 203.67
Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as morphinan-6-ol, 7,8-didehydroxy-4,5-epoxy-3-methoxy-17-methyl-, (5α,6α)-, phosphate (1:1) (salt), hemihydrate. The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. Its structure is as follows:
C18H21NO3 • H3PO4 • ½ H2O M.W. 406.37
Brompheniramine Maleate is classified as an alkylamine antihistamine. This class is among the most active histamine antagonists and is generally effective in relatively low milligram doses. Alkylamines cause a lesser degree of drowsiness and sedation than the phenothiazine antihistamines and hence may be more suitable for daytime use. It should be noted, however, that patients taking alkylamine antihistamines may experience some degree of drowsiness.
Phenylephrine Hydrochloride is a sympathomimetic amine which acts predominantly by a direct action on alpha (α)-adrenergic receptors. In therapeutic doses, the drug has no significant stimulant effect on the beta (β)- adrenergic receptors of the heart. Clinically, Phenylephrine HCl shrinks swollen mucous membranes, reduces tissue hyperemia, edema, and nasal congestion; and increases nasal airway patency. In therapeutic doses the drug causes little, if any, central nervous system (CNS) stimulation.
Narcotic analgesics, including codeine, exert their primary effects on the central nervous system and gastrointestinal tract. The analgesic effects of codeine are due to its central action; however, the precise sites of action have not been determined, and the mechanisms involved appear to be quite complex. Codeine resembles morphine both structurally and pharmacologically, but its actions at the doses of codeine used therapeutically are milder, with less sedation, respiratory depression, and gastrointestinal, urinary, and pupillary effects. Codeine produces an increase in biliary tract pressure, but less than morphine or meperidine. Codeine is less constipating than morphine. Codeine has good antitussive activity, although less than that of morphine at equal doses. It is used in preference to morphine, because side effects are infrequent at the usual antitussive dose of codeine. Codeine in oral therapeutic dosage does not usually exert major effects on the cardiovascular system. Narcotic analgesics may cause nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ); however, they also depress the vomiting center, so that subsequent doses are unlikely to produce vomiting. Nausea is minimal after usual oral doses of codeine. Narcotic analgesics cause histamine release, which appears to be responsible for wheals or urticaria sometimes seen at the site of injection on parenteral administration. Histamine release may also produce dilation of cutaneous blood vessels, with resultant flushing of the face and neck, pruritus, and sweating.
Codeine and its salts are well absorbed following both oral and parenteral administration. Codeine is about 2/3 as effective orally as parenterally. Codeine is metabolized primarily in the liver by enzymes of the endoplasmic reticulum, where it undergoes 0-demethylation, N-demethylation, and partial conjugation with glucuronic acid. The drug is excreted primarily in the urine, largely as inactive metabolites and small amounts of free and conjugated morphine. Negligible amounts of codeine and its metabolites are found the feces. Following oral or subcutaneous administration of codeine, the onset of analgesia occurs within 15 to 30 minutes and lasts for four to six hours. The cough-depressing action, in animal studies, was observed to occur 15 minutes after oral administration of codeine, peak action at 45 to 60 minutes after ingestion. The duration of action, which is dose-dependent, usually did not exceed 3 hours.
TL-HIST CD Liquid is indicated for the temporary relief of runny nose, sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever or other upper respiratory allergies or allergic rhinitis; for the symptomatic relief of respiratory conditions characterized by dry, non-productive cough and in the presence of tenacious mucus and/or mucus plugs in the respiratory tract; nonnarcotic cough suppressant for the temporary control of cough due to minor throat and bronchial irritation associated with the common cold or inhaled irritants; calms the cough control center and relieves coughing.
This drug is contraindicated in patients who are sensitive to any of the ingredients or related compounds. Patients known to be hypersensitive to other sympathomimetic amines may exhibit cross sensitivity with Phenylephrine. Phenylephrine is contraindicated in patients with hypertension or ventricular tachycardia and should be employed only with extreme caution in elderly patients or in patients with hyperthyroidism, bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis. Phenylephrine is contraindicated in patients on monoamine oxidase inhibitor (MAOI) therapy and for 14 days after stopping MAOI therapy.
Codeine is contraindicated in patients with a known hypersensitivity to the drug.
Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma. Antihistamines and anticholinergics are contraindicated in patients with narrow angle glaucoma, urinary retention, peptic ulcer and during an asthma attack.
Contraindicated in breast-feeding mothers.
Do not exceed recommended dosage. If nervousness, dizziness, or sleeplessness occur, discontinue use and consult a doctor.
When using this product, TL-HIST CD Liquid may cause marked drowsiness.
A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by a fever, rash, or persistent headache, consult a doctor. Do not take this product for persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis, or emphysema, or where cough is accompanied by excessive phlegm (mucus) unless directed by a physician. Antihistamines should be used with caution in patients with narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, and urinary bladder neck obstruction. Antihistamines and/or decongestants may cause excitability, particularly in children. At doses higher than the recommended dose, nervousness, dizziness, or sleeplessness may occur. Patients sixty (60) years and older may demonstrate an increased response to this drug combination, both in therapeutic effect and in the incidence of adverse reactions and hence a lower dose may be more appropriate for these patients.
Sympathomimetic amines should be used judiciously and sparingly in patients with hypertension, diabetes mellitus, ischemic heart disease, increased intraocular pressure, hyperthyroidism, or prostatic hypertrophy. Sympathomimetics may produce CNS stimulation and convulsions or cardiovascular collapse with accompanying hypotension.
Hypertensive crises can occur with concurrent use of Phenylephrine and MAO inhibitor, and for 14 days after stopping MAO inhibitor therapy, indomethacin, or with beta blockers and methyldopa. If a hypertensive crisis occurs, these drugs should be discontinued immediately and therapy in lower blood pressure should be instituted. Fever should be managed by means of external cooling.
Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.
Codeine may cause or aggravate constipation.
Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussive in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.
Administration of codeine may be accomplished by histamine release and should be used with caution in atopic children.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a reexisting increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.
Asthma and Other Respiratory Conditions
Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients. Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.
Before prescribing medication to suppress or modify cough, it is important that the underlying cause of cough is identified, that modification of cough does not increase the risk of clinical or physiological complications, and that appropriate therapy for the primary disease is instituted. Antihistamines have an atropine-like action and, therefore should be used with caution in patients with a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease and hypertension.
Phenylephrine containing preparations should be used with caution in the presence of hypertension; coronary artery disease; any other cardiovascular disease; glaucoma; prostatic hypertrophy; hyperthyroidism; diabetes. Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients.
Ultra-rapid Metabolizers of Codeine
Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2×2 genotype. 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 regiments, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose.
Drug/Laboratory Test Interactions
Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
Antihistamines may interfere with diagnostic test results for skin tests using allergen extracts.
Concurrent use of tricyclic antidepressants may antagonize the effects of Phenylephrine. MAO inhibitors and beta adrenergic blockers increase the effect of sympathomimetics.
Sympathomimetics may reduce the antihypertensive effects of methyldopa, mecamylamine, reserpine, and veratrum alkaloids. Care should be taken in administering TL-HIST CD Liquid concomitantly with other sympathomimetic amines, since their combined effects on the cardiovascular system may be harmful to the patient.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No data are available on the long-term potential for carcinogenesis, mutagenesis, or impairment of fertility in animals or humans.
Pregnancy Category C
A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no studies in humans, and the significance of these findings to humans, if any, is not known.
Labor and Delivery
Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required.
Certain antihistamines and sympathomimetics are known to be excreted in breast milk. Use of this product by nursing mothers is not recommended because of the higher than usual risk for infants from sympathomimetic amines.
Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding.
Information for Patients
Patients should be instructed to check with physician if symptoms do not improve within 7 days or if fever is present. Patient consultation should include the following information regarding proper use of this medication: Do not take more medication than the amount recommended; take medication with food, water, or milk to minimize gastric irritation; do not drive or operate machinery if drowsiness or dizziness occurs; do not ingest alcoholic beverages, monoamine oxidase inhibitors, or CNS depression-producing medications (hypnotics, sedatives, tranquilizers) while taking this medication; if a dose is missed, the medication should be taken as soon as possible unless it is almost time for the next dose; not doubling doses; this medication should be stored in a tight, light-resistant container at temperatures between 15°-30°C (59°-86°F); keep all medications out of the reach of children. In case of accidental overdose, seek professional assistance or contact a poison control center immediately. Codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from codeine therapy.
The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics, and tranquilizers, may have an additive effect and should be avoided or their dosage reduced.
Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly. Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Nursing mothers taking codeine can also have higher morphine levels in their breast milk of they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).
Use in the Elderly
Confusion, dizziness, sedation, hypotension, hyperexcitability, and anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), may be more likely to occur in geriatric patients taking antihistamines. The elderly (60 years and older) are more likely to have adverse reactions to sympathomimetics. Overdosage of sympathomimetics in this age group may cause hallucinations, convulsions, CNS depression and death.
Sedation; dizziness; headache; nervousness; excitability in children (rare); Diplopia; vomiting; diarrhea; dry mouth; nausea; anorexia; heartburn; Polyuria; dysuria; urinary retention in patients with prostatic hypertrophy, weakness.
Hyperreactive individuals may display ephedrine-like reactions such as tachycardia, palpitations, headache, dizziness, or nausea. Sympathomimetic amines have been associated with certain untoward reactions including fear, anxiety, nervousness, restlessness, tremor, weakness, pallor, respiratory difficulty, dysuria, insomnia, hallucinations, convulsions, CNS depression, arrhythmias, and cardiovascular collapse with hypotension.
Nervous System - CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, transient hallucination, disorientation, visual disturbances, and convulsions.
Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics).
Gastrointestinal – Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported.
Genitourinary – Oliguria, urinary retention, antidiuretic effect has been reported (common to narcotic analgesics).
Allergic – Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema.
Other – Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness.
DRUG ABUSE AND DEPENDENCE
TL-HIST CD Liquid is subject to Federal Controlled Substances Act (Schedule V).
Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only under close supervision to patients with a history of drug abuse or dependence.
Overdosage with antihistamines may cause hallucinations, convulsions or possible death, especially in children. Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients. Treatment of acute overdosage would probably be based upon treating the patient for the symptoms of overdosage of Phenylephrine HCl as follows: The treatment of overdosage should provide symptomatic and supportive care. If the amount ingested is considered dangerous or excessive, induce vomiting with ipecac syrup unless the patient is convulsing, comatose, or has lost the gag reflex, in which case perform gastric lavage using a large bore tube. If indicated, follow with activated charcoal and a saline cathartic.
Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils, and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates.
Treatment of overdosage with codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patient airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with codeine; Severe hypotension usually responds to the administration of norepinephrine or Phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Limited experience with dialysis indicates that it is not helpful.
DOSAGE AND ADMINISTRATION
Adults and children over 12 years of age
1 teaspoonful (5 mL) by mouth every 4-6 hours not to exceed 6 teaspoonfuls in 24 hours.
Children 6 to under 12 years
½ teaspoonful (2.5 mL) by mouth every 4-6 hours not to exceed 3 teaspoonfuls in 24 hours.
Shake liquid well before use.
Also contains the following inactive ingredients (in alphabetical order): Citric Acid, Cotton Candy Flavor, Methyl Paraben, Potassium Citrate, Potassium Sorbate, Propyl Paraben, Propylene Glycol, Purified Water, Sorbitol Solution 70%, Sucralose
TL-HIST CD Liquid is a clear solution with a cotton candy flavor which contains 4 mg Brompheniramine Maleate, 7.5 mg Phenylephrine HCl, 10 mg Codeine Phosphate, available in 16 fl oz (473 mL) bottles.
WARNING: KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY.
Dispense in a tight, light-resistant container as defined in USP/NF with a child-resistant closure.
Store at controlled room temperature 15°-30°C (59°-86°F).
PRINCIPAL DISPLAY PANEL - 473 mL Bottle Label
Antihistamine • Decongestant
Each 5 mL (1 teaspoonful) of
16 fl oz (473 mL)
Revised: 11/2010 TRIGEN Laboratories, Inc.
Reproduced with permission of U.S. National Library of Medicine
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