Covan Syrup Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults COVAN (triprolidine hydrochloride /pseudoephedrine hydrochloride/codeine phosphate) is indicated for the temporary relief of coughs associated with allergy or the common cold.

Geriatrics (> 65 years of age)

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy.

Pediatrics (< 18 years of age)

COVAN is contraindicated in patients younger than 18 years of age because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine and because the benefits of symptomatic treatment of cough do not outweigh the risks for use of codeine in these patients (see also CONTRAINDICATIONS; and DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

COVAN is contraindicated in:

• Pediatric patients (under the age of 18 years) (see WARNINGS AND PRECAUTIONS; Special Populations; Pediatrics (< 18 years of age)).
• Women who are breastfeeding, pregnant or during labour and delivery (see SERIOUS WARNINGS AND PRECAUTIONS, and WARNINGS AND PRECAUTIONS).
• Patients who are known to be CYP2D6 extensive or ultra-rapid metabolisers for whom there is an increased risk of developing symptoms of opioid toxicity, even at commonly prescribed doses (see WARNINGS AND PRECAUTIONS, Ultra-Rapid Metabolizers of Codeine).
• Patients who are hypersensitive to the active substances: codeine phosphate or other opioid analgesics; triprolidine hydrochloride, or other antihistamines of similar chemical structure; sympathomimetic amines including pseudoephedrine hydrochloride; or to any ingredient in the formulation. COVAN contains methylparaben. It is contraindicated in patients with hypersensitivity to parabens. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Prescribing Information.
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).
• Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus.
• Patients with chronic or persistent cough, such as what occurs with asthma, smoking or emphysema, or where cough is accompanied by excessive secretions (eg. bronchiectasis).
• Patients receiving any other sympathomimetics, such as decongestants, appetite suppressants, and amphetamine-like psychostimulants.
• Patients with acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale.
• Patients with hypertension or coronary artery disease.
• Patients with acute alcoholism, delirium tremens, and convulsive disorders.
• Patients with severe hepatic impairment, as it may precipitate hepatic encephalopathy.
• Patients with moderate to severe renal impairment (glomerular filtration rate less than 60 mL/min).
• Patients with pheochromocytoma.
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
• Patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
• Patients with ulcerative colitis. As other opioid analgesics, codeine may precipitate toxic dilatation or spasm of the colon.
• Patients in, or at risk of developing respiratory failure.

WARNINGS AND PRECAUTIONS

General

Before prescribing medication to suppress or modify cough, it is important to ascertain that the underlying cause of the cough is identified, that modification of the cough does not increase the risk of clinical or physiological complications, and that appropriate therapy for the primary disease is provided.

Accidental ingestion, especially by children can result in a fatal overdose of codeine (see DOSAGE AND ADMINISTRATION, Disposal, for instructions on proper disposal).

Patients should be advised to seek medical advice if symptoms persist for more than 3 days.

Patients should be cautioned not to consume alcohol while taking COVAN as it may increase the chance of experiencing serious adverse events, including death.

COVAN should not be used in patients with a history of arrhythmia, epilepsy, increased intraocular pressure (narrow angle glaucoma), prostatic hypertrophy, bladder neck obstruction, diabetes mellitus, cardiovascular disease and hyperthyroidism, unless its benefits outweigh its risks in these patients.

COVAN contains 3.0 g of sucrose per 5 mL. COVAN should be used with considerable caution in patients with diabetes mellitus.

COVAN should be prescribed with caution for certain special at risk patients such as the elderly and debilitated, for those with gallbladder disease or gallstones, history of bronchial asthma, or urethral stricture.

Patients' self-medication should be assessed. COVAN should not be used by patients intolerant to sympathomimetics used for the relief of nasal or sinus congestion. Such drugs include ephedrine, epinephrine, phenylpropanolamine and phenylephrine. Symptoms of intolerance include drowsiness, dizziness, weakness, difficulty in breathing, tenseness, muscle tremors or palpitations.

COVAN should be used with caution in patients taking the following medications: metoclopramide, domperidone, and central nervous system depressants, including alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazine (see DRUG INTERACTIONS).

Abuse and Misuse

Like all opioids, COVAN is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, COVAN should be prescribed and handled with caution. Therefore, COVAN should be prescribed and handled with caution.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.

Opioids, such as COVAN, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Use in Drug and Alcohol Addiction

COVAN is an opioid with no approved use in the management of pain. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of cough requiring opioids. Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to COVAN; extreme caution and awareness is warranted to mitigate the risk.

Carcinogenesis and Mutagenesis

See TOXICOLOGY section.

Cardiovascular

Codeine administration may result in hypotension and dizziness. COVAN should be used with caution in patients taking beta-blockers or other anti-hypertensives.

Dependence/Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated administration of COVAN and there is a potential for development of psychological dependence. Patients should take the drug only for as long, in the amounts, and as frequently as prescribed.

Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Endocrine

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Gastrointestinal Effects

COVAN should not be used in patients with obstructive bowel disorder or acute abdominal conditions (i.e. acute appendicitis or pancreatitis), stenosing peptic ulcer or pyloroduodenal obstruction, unless its benefits outweigh its risks in these patients.

Patients with a history of cholecystectomy should consult a doctor before using COVAN as it may cause acute pancreatitis in some patients.

Codeine and other morphine-like opioids have been shown to decrease bowel motility. Codeine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

There have been reports of ischemic colitis with pseudoephedrine. COVAN should be discontinued immediately and medical advice sought if sudden abdominal pain, rectal bleeding or other symptoms of ischemic colitis develop.

Head Injury

The respiratory depressant effects of codeine, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, codeine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, codeine must be used with extreme caution and only if it is judged essential (see CONTRAINDICATIONS).

Immune

Large doses of codeine may cause the release of significant quantities of histamine, which may be associated with hypotension, cutaneous vasodilation, urticaria and, more rarely, bronchoconstriction.

Neonatal Opioid Withdrawal Syndrome (NOWS)

Use of COVAN is contraindicated in pregnant women (see CONTRAINDICATIONS).

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Neurologic

Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol): Concomitant use of opioids, including COVAN, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol (see DRUG INTERACTIONS).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if COVAN is used with benzodiazepines, alcohol, or other CNS depressants.

There have been rare cases of posterior reversible encephalopathy (PRES)/reversible cerebral vasoconstriction syndrome (RCVS) reported with sympathomimetic drugs, including pseudoephedrine. Symptoms reported included sudden onset of severe headache, nausea, vomiting, and visual disturbances. Most cases improved or resolved within a few days following appropriate treatment. Pseudoephedrine should be discontinued immediately and medical advice sought if signs/symptoms of PRES/RCVS develop.

Serotonin syndrome: COVAN could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g. anti-depressants, migraine medications). Treatment with the serotonergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. COVAN should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see DRUG INTERACTIONS).

Psychomotor Impairment

COVAN may seriously impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of codeine with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.

COVAN may impair performance in tests of auditory vigilance. There is individual variation in response to antihistamines. Codeine may cause drowsiness or dizziness. The anticholinergic properties of triprolidine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery.

Respiratory

Codeine, including COVAN, is not recommended for use in any patient in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, lung infections, multiple trauma or extensive surgical procedures.

Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Codeine should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see CONTRAINDICATIONS).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of COVAN, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with COVAN and following dose increases.

Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Risk of Death in Ultra-Rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 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 regimens, 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, Japanese and 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. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose (see DOSAGE AND ADMINISTRATION, Dosing Considerations).

Risk factors for life-threatening respiratory depression in children

Respiratory depression and death have occurred in children who received codeine in the postoperative 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 2D6 or high morphine concentrations). COVAN is contraindicated for patients younger than 18 years of age (see CONTRAINDICATIONS).

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with COVAN requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine (see DRUG INTERACTIONS).

Use in Patients with Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with COVAN, as in these patients, even usual therapeutic doses of COVAN may decrease respiratory drive to the point of apnea. The use of COVAN is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).

Sexual Function/Reproduction

Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Special Populations

Special Risk Groups: Codeine should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison’s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture.

Pregnant Women: Studies in humans have not been conducted. While animal reproduction studies have revealed no evidence of harm to the fetus due to triprolidine/pseudoephedrine/codeine (see TOXICOLOGY), COVAN does cross the placental barrier. Thus, COVAN is contraindicated in pregnant women.

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome (NOWS), unlike opioid withdrawal syndrome in adults, can be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome).

Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.

Labour, Delivery and Nursing Women: Since opioids can cross the placental barrier and are excreted in breast milk, COVAN is contraindicated during labour and delivery or in nursing mothers. Administration of opioids during labour may produce gastric stasis and increase the risk of vomiting and aspiration pneumonia in the mother. Life-threatening respiratory depression can occur in the infant if opioids are administered during labour. Naloxone, a drug that counters the effects of opiates, should be readily available if COVAN is used in this population.

No clinical data on exposed pregnancies are available for COVAN. Animal studies with pseudoephedrine and triprolidine do not indicate direct or indirect harmful effects on embryofetal development (see TOXICOLOGY section).

Use in Lactation

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. However, some women are ultra-rapid metabolisers of codeine (see CONTRAINDICATIONS, Ultra-Rapid Metabolisers of Codeine; and WARNINGS AND PRECAUTIONS; Ultra-Rapid Metabolisers 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 breast-fed infants. 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 breast-feeding, breathing difficulties, and decreased tone, in their baby. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death in nursing infants.

Since there is a risk of infant exposure to codeine and morphine through breast milk, COVAN is contraindicated in breast-feeding. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about any use of codeine during breast-feeding.

Geriatrics (> 65 years of age):

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The elderly may be more susceptible to adverse effects and are more likely to experience neurological anticholinergic effects and paradoxical excitation (see DOSAGE AND

ADMINISTRATION).

Pediatrics (< 18 years of age):

COVAN is contraindicated in patients younger than 18 years of age because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine and because the benefits of symptomatic treatment of cough do not outweigh the risks for use of codeine in these patients (see INDICATIONS, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION).

Patients with Hepatic Impairment:

Experience with the use of the product suggests that normal adult dosage is appropriate in the presence of mild to moderate hepatic impairment, although it may be prudent to exercise caution (see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS).

There have been no specific studies of COVAN, triprolidine, pseudoephedrine or codeine in hepatic impairment.

Patients with Renal Impairment:

Caution should be exercised when administering COVAN to patients with mild renal impairment, particularly if accompanied by cardiovascular disease (see CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION).

There have been no specific studies of COVAN, triprolidine or codeine in renally impaired patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In some patients, nervousness, insomnia, sedation, drowsiness, dizziness, disturbance in attention, abnormal coordination, dry mouth nose and throat, nausea, and vomiting may occur.

Triprolidine

Triprolidine may cause sedation, drowsiness, dizziness, disturbance in attention and abnormal coordination. Skin rashes, with or without irritation, have occasionally been reported. Dryness of the mouth, nose and throat may occur. Tachycardia, paradoxical excitation*, confusion**, nightmares***, hallucinations***, blurred vision, thickening of bronchial secretions, urinary retention, rash, urticaria and gastrointestinal disturbance including nausea and vomiting may also occur.

* Children and the elderly are more susceptible to paradoxical excitation (e.g. increased energy, restlessness, nervousness).

** The elderly are more prone to confusion.

***Hallucinations and nightmares have been reported mainly in children

Pseudoephedrine

Symptoms of central nervous system excitation may occur, including nervousness, agitation, restlessness, sleep disturbance, dizziness, and rarely, hallucinations. Dryness of the mouth, nausea, and vomiting may occur. Skin rashes, with or without irritation, have occasionally been reported with pseudoephedrine. Urinary retention has been reported occasionally in men receiving pseudoephedrine; prostatic enlargement could have been an important predisposing factor. Dysuria, increased blood pressure (not clinically significant at therapeutic doses), allergic dermatitis (a variety of allergic skin reactions, with or without systemic features such as bronchospasm, angioedema have been reported following use of pseudoephedrine), tachycardia and palpitations may also occur.

Codeine

In some patients, dizziness, worsening of headache with prolonged use, drowsiness, pruritis and sweating may occur.

In therapeutic doses, codeine is less likely than morphine to produce adverse effects. The most common adverse effects noted with codeine include nausea, vomiting, dyspepsia, and constipation. Micturition may be difficult. Dry mouth, vertigo, light-headedness, tachycardia, rash and urticaria also occur. These effects occur more commonly in ambulant patients than those at rest in bed. Therapeutic doses of codeine occasionally induce hallucinations. Acute pancreatitis in patients with a history of cholecystectomy and symptoms of central nervous system depression may also occur.

Post-Marketing Experience

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

DRUG INTERACTIONS

Overview

COVAN should not be used with other cough and cold medications with an antihistamine, sympathomimetic, and antitussive.

Because of its pseudoephedrine content, COVAN may interact with drugs acting on the cardiovascular system, including bretylium, guanethidine, methyldopa, and alpha- and beta-adrenergic blocking agents.

Concomitant administration of pseudoephedrine hydrochloride and MAOIs (or within two weeks of stopping an MAOI) may lead to hypertensive crisis. The anticholinergic effects of triprolidine are intensified by MAOIs (see CONTRAINDICATIONS).

Opiate analgesics may interact with monoamine oxidase inhibitors (MAOI) and result in serotonin syndrome (see CONTRAINDICATIONS).

Concomitant use of COVAN with tricyclic antidepressants, triptans, or with sympathomimetic agents (such as decongestants, appetite suppressants and amphetamine-like psychostimulants), which interfere with the catabolism of sympathomimetic amines, may cause a rise in blood pressure.

Codeine, like other opioids, may antagonise the effects of metoclopramide and domperidone on gastrointestinal motility.

Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants (including alcohol):

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) increases the risk of respiratory depression, profound sedation, coma, and death and should be avoided. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS AND PRECAUTIONS, Neurologic, Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol) and Psychomotor Impairment). COVAN should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.

Drugs Associated with a Risk of Serotonin Syndrome:

Coadministration of codeine with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may increase the risk of serotonin syndrome, a potentially life-threatening condition (see WARNINGS AND PRECAUTIONS).

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes:

The effects of concomitant use or discontinuation of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex, and requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of COVAN while taking CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals or for signs of opioid withdrawal.

CYP2D6 inhibitors: The concomitant use of COVAN and CYP2D6 inhibitors (e.g., amiodarone, quinidine) may result in a decrease in active metabolite morphine plasma concentration, leading to decreased efficacy or symptoms of opioid withdrawal. The discontinuation of a concomitantly used CYP2D6 inhibitor may lead to an increased metabolism to morphine, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

CYP3A4 inhibitors: The concomitant use of COVAN and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir) can increase the plasma concentration of codeine and its subsequent metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong opioid effects. The discontinuation of a concomitantly used CYP3A4 inhibitor might results in a reduced efficacy of COVAN.

CYP3A4 inducers: The concomitant use of COVAN and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, may result in a decreased plasma concentration of codeine and its active metabolite morphine, leading to decreased efficacy or symptoms of opioid withdrawal. The discontinuation of concomitantly used CYP3A4 inducers can increase the plasma concentration of codeine and its active metabolite morphine, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Drug-Laboratory Interactions

Opioid analgesics may interfere with certain diagnostic procedures, by increasing plasma amylase and lipase concentrations and by increasing CSF pressure. Gastric emptying is delayed by these drugs so gastric emptying studies will not be valid.

Drug-Lifestyle Interactions

The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS, General).

DOSAGE AND ADMINISTRATION

Pediatrics (< 18 years of age):

COVAN is contraindicated in patients younger than 18 years of age because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine and because the benefits of symptomatic treatment of cough do not outweigh the risks for use of codeine in these patients.

Increasing Risk with Higher Doses

All doses of opioids carry an inherent risk of fatal or non-fatal adverse events. This risk is increased with higher doses. COVAN should not be administered for more than 3 days. The maximum recommended daily dose of COVAN is 40 mL, which is 80 mg codeine (12 morphine milligram equivalent) for adults over the age of 18 years. Each patient should be assessed for their risk prior to prescribing COVAN, as the likelihood of experiencing serious adverse events can depend upon the type of opioid and duration of treatment, as well as the patient’s own level of tolerance. In addition, the coughing should be assessed routinely to confirm the most appropriate dose and the need for further use of COVAN (see DOSAGE AND ADMINISTRATION - Adjustment or Reduction of Dosage).

Dosing Considerations

COVAN should be avoided in patients known or suspected to be ultra-rapid CYP2D6 metabolizers. Patients should be advised to seek medical advice if symptoms persist for more than 3 days. Do not increase the dose or the frequency of dosing.

Avoid use with other decongestants, anti-histamine-containing or other codeine containing products, including cough and cold medicines (see WARNINGS AND PRECAUTIONS).

Recommended Dose and Dosage Adjustment

Adults:

Take 10 mL of syrup every 6-8 hours as required. Do not exceed 4 doses in a day (24 hours). Minimum time between doses: 6 hours

Codeine, including COVAN, should be prescribed at the lowest effective dose for the shortest period of time. Dosing should be as needed and not on scheduled intervals.

Patients with Hepatic Impairment:

Experience with the use of the product suggests that normal adult dosage is appropriate in the presence of mild to moderate hepatic impairment. COVAN is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).

There have been no specific studies of COVAN, triprolidine, pseudoephedrine or codeine in hepatic impairment.

Patients with Renal Impairment:

Caution should be exercised when administering COVAN to patients with mild to moderate renal impairment, particularly if accompanied by cardiovascular disease (see CONTRAINDICATIONS). COVAN is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS).

There have been no specific studies of COVAN, triprolidine, pseudoephedrine or codeine in renally impaired patients.

Geriatrics:

Respiratory depression has occurred in the elderly following administration of large initial doses of opioids to patients who were not opioid-tolerant or when opioids were co-administered with other agents that can depress respiration. COVAN should be initiated at a low dose and slowly titrated to effect (see WARNINGS AND PRECAUTIONS).

Although there have been no specific studies of COVAN in this group of patients, it may be anticipated that the elderly may be more susceptible to adverse effects. Therefore, reduced dosage and careful monitoring is advised, particularly in cases where there is impairment of renal, hepatic or mental status (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Adjustment or Reduction of Dosage:

Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including COVAN. Withdrawal (abstinence) symptoms may occur following abrupt discontinuation of prolonged therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

Missed Dose

As there is no strictly scheduled dosing (see Recommended Dose and Dosage Adjustment; Adults), COVAN should be administered as needed for cough and should not exceed 4 doses in a day (24 hours).

If the patient forgets to take one or more doses, they should take their next dose at the next scheduled time and in the normal amount.

Disposal

COVAN should be kept in a safe place, out of the sight and reach of children before, during and after use. COVAN should not be used in front of children, since they may copy these actions.

COVAN should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended. Unused or expired COVAN should be properly disposed of as soon as it is no longer needed to prevent accidental exposure to others, including children or pets). If temporary storage is required before disposal, a sealed child-proof container, such as a biohazard waste container or lockable medication box could be obtained from a pharmacy.

OVERDOSAGE

Symptoms

In children, the ingredients, in overdosage, may produce hallucinations, convulsions and death. Symptoms of toxicity in children may include fixed dilated pupils, flushed face, dry mouth, fever, excitation, hallucinations, ataxia, incoordination, athetosis, tonic clonic convulsions, and postictal depression.

In addition to the undesirable effects seen with recommended doses, overdosage with codeine can cause transient euphoria, drowsiness, dizziness, weariness, diminution of sensibility, loss of sensation, vomiting, transient excitement in children and occasionally in adults, miosis progressing to nonreactive pinpoint pupils, itching sometimes with skin rashes and urticaria, and clammy skin with mottled cyanosis. In more severe cases, muscular relaxation with depressed or absent superficial and deep reflexes and a positive Babinski sign may appear. Marked slowing of the respiratory rate with inadequate pulmonary ventilation and consequent cyanosis may occur along with drowsiness, ataxia and, more rarely, pulmonary oedema, respiratory pauses, miosis, convulsion, collapse and urine retention. Terminal signs include shock, pulmonary edema, hypostatic or aspiration pneumonia and respiratory arrest, with death occurring within 6 to 12 hours following ingestion. Signs of histamine release have been observed.

Overdoses of antihistamines may cause hallucinations, convulsions or possibly death, especially in children. Antihistamines are more likely to cause dizziness, sedation and hypotension in elderly patients. Overdosage with triprolidine is likely to result in effects similar to those listed under adverse reactions and may produce reactions varying from depression to stimulation of the 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. Additional symptoms may include ataxia, weakness, respiratory depression, dryness of the skin and mucous membranes, hyperpyrexia, tremor, psychosis, and convulsions.

Overdosage with pseudoephedrine can cause excessive CNS stimulation resulting in excitement, nervousness, anxiety, tremor, restlessness and insomnia. Other effects include tachycardia, hypertension, pallor, mydriasis, hyperglycemia and urinary retention. Severe overdosage may cause psychosis, tachypnea or hyperpnea, hallucinations, hypertensive crisis, convulsions or delirium, but in some individuals there may be CNS depression with coma, somnolence, stupor or respiratory depression. Arrhythmias (including ventricular fibrillation) may lead to hypotension and circulatory collapse. Severe hypokalemia can occur, probably due to compartment shift rather than depletion of potassium. No organ damage or significant metabolic derangement is associated with pseudoephedrine overdosage.

Treatment

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, gastric lavage is indicated. Adequate precautions must be taken to protect against aspiration, especially in children. Charcoal slurry or other suitable agents should be instilled into the stomach after vomiting or lavage. Saline cathartics or milk of magnesia may be of additional benefit.

In the unconscious patient, the airway should be secured with a cuffed endotracheal tube before 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 of respiration is the most effective means of providing adequate oxygenation.

Hypotension is an early sign of impending cardiovascular collapse and should be treated vigorously.

Do not use CNS stimulants. Convulsion 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, while naloxone is useful as a codeine antidote. Close nursing care is essential.

Saline cathartics, such as milk of magnesia, help to dilute the concentration of the drugs in the bowel by draining 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. Histamine should not be given.

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

In severe cases of overdosage, it is essential to monitor both the heart by ECG and plasma electrolytes and to give i.v. potassium as indicated by these continuous controls. Vasopressors may be used to treat hypotension, and excessive CNS stimulation may be counteracted with parenteral diazepam. Stimulants should not be used.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

Pseudoephedrine

Pseudoephedrine has direct and indirect sympathomimetic activity and is an effective upper respiratory decongestant. Pseudoephedrine is less potent than ephedrine in producing both tachycardia and elevation of systolic blood pressure and is also less potent in causing stimulation of the central nervous system. Pseudoephedrine produces its decongestant effect within 30 minutes, persisting for at least 4 hours.

Triprolidine

Triprolidine is a potent, competitive histamine H₁-receptor antagonist. Being an alkylamine, the drug possesses minimal anticholinergic activity. Triprolidine provides symptomatic relief in conditions believed to depend wholly, or partly, upon the triggered release of histamine. After oral administration of a single dose of 2.5 mg triprolidine to adults, the onset of action, as determined by the ability to antagonise histamine-induced wheals and flares in the skin, was within 1 to 2 hours. Peak effects occurred at about 3 hours, and although activity declined thereafter, significant inhibition of histamine-induced wheals and flares still occurred 8 hours after a single dose.

Codeine

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite, which is an agonist of opiate receptors and possesses analgesic, antitussive, and antidiarrheal actions.

Central Nervous System:

Codeine produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.

Codeine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Codeine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of codeine overdose.

Gastrointestinal Tract and Other Smooth Muscle:

Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System:

Codeine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.

Endocrine System:

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.

Immune System:

In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.

Pharmacokinetics

Absorption:

Pseudoephedrine, triprolidine and codeine are well absorbed from the gut following oral administration.

Triprolidine and Pseudoephedrine

After the administration of 10 mL ACTIFED syrup (containing 2.5 mg triprolidine hydrochloride and 60 mg pseudoephedrine hydrochloride) to healthy adult volunteers,

• the peak plasma concentration (C_max) of triprolidine was 6.0 ng/mL, occurring at about 1.5 hours after drug administration
• the C_max of pseudoephedrine was approximately 180 ng/mL, with T_max occurring at approximately 1.5 hours after drug administration

Codeine

Following oral administration, peak plasma concentrations occur in approximately 1 hour. Maximum plasma concentrations of codeine are in the range of 100 to 300 ng/mL following normal therapeutic doses.

Distribution:

The apparent volumes of distribution (Vd/F) are approximately:

• 7.5 L/kg for triprolidine
• 2.8 L/kg for pseudoephedrine
• 3.6 L/kg for codeine

Metabolism and Excretion:

Triprolidine

The plasma half-life (t½) of triprolidine was approximately 3.2 hours. Animal hepatic microsomal enzyme studies have revealed the presence of several triprolidine metabolites with an oxidized product of the toluene methyl group predominating. In man, it has been reported that only about 1% of an administered dose is eliminated as unchanged triprolidine over a 24-hour period. The apparent total body clearance of triprolidine (Cl/F) was approximately 30 to 37 mL/min/kg. The elimination rate constant (Kcl) was approximately 0.26 hr^-1.

Pseudoephedrine

The plasma half-life (t½) was approximately 5.5 hours. Pseudoephedrine is partly metabolised in the liver by N-demethylation to norpseudoephedrine, an active metabolite. Pseudoephedrine and its metabolite are excreted in the urine; 55% to 90% of a dose is excreted unchanged. The apparent total body clearance of pseudoephedrine (Cl/F) was approximately 7.5 mL/min/kg. The elimination rate constant (Kcl) was approximately 0.13 hr^-1. The rate of urinary elimination is accelerated when the urine is acidified. Conversely, as the urine pH increases, the rate of urinary excretion is slowed.

Codeine

The plasma half-life (t½) of codeine was approximately 3 to 4 hours.

Codeine is metabolised by the liver enzyme CYP2D6 via O-demethylation to form morphine, and via N-demethylation to form norcodeine. Codeine and its metabolites are also glucuronidated and sulphated in the liver.

Individuals who are heterozygous for the CYP2D6*2A allele are classified as ultra-rapid metabolisers of codeine. In these patients CYP2D6 enzyme is induced and O-demethylation of codeine to morphine is increased. If the patient is an extensive or ultra-rapid metaboliser, there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses (see CONTRAINDICATIONS).

After an oral dose, about 86% is excreted in the urine in 24 hours as free drug and metabolites, the majority as metabolites. Trace amounts of codeine are found in the feces. Unchanged drug accounts for 6 to 8% of the dose in urine in 24 hours, which may be increased to about 10% when the urinary pH is decreased.

STORAGE AND STABILITY

Store between 15°C and 30°C. Protect from light. Keep out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each 5 mL of clear, dark red syrupy liquid with a mixed fruit odour contains: triprolidine HCl 2 mg, pseudoephedrine HCl 30 mg and codeine phosphate 10 mg. Also contains artificial raspberry flavour, FD&C red #2, glycerin, methylparaben, purified water, sodium benzoate, sodium saccharin and sucrose. Alcohol-free. Bottles of 100 mL and 500 mL

PART II: SCIENTIFIC INFORMATION

TOXICOLOGY

Mutagenicity

Triprolidine was not mutagenic in bacterial cells in an Ames test.

Pseudoephedrine is not genotoxic in a battery of in vivo and in vitro tests in bacterial and mammalian assay systems.

Codeine was not mutagenic in bacterial cells in vitro, or in an in vivo mouse micronucleus test.

Carcinogenicity

Triprolidine and codeine were not carcinogenic in assays performed in mice and rats.

There is insufficient information available to determine whether pseudoephedrine has carcinogenic potential.

Teratogenicity

Triprolidine did not produce teratogenic effects at oral doses of up to 125 mg/kg/day in the rat, or 100 mg/kg/day in the rabbit.

Pseudoephedrine did not produce teratogenic effects at oral doses of up to 432 mg/kg/day in the rat, or 200 mg/kg/day in the rabbit.

Codeine did not produce teratogenic effects at oral doses of up to 120 mg/kg/day in the rat, or 30 mg/kg/day in the rabbit. However, at 120 mg/kg/day there was an increase in mortality in rat embryos near the period of implantation.

Fertility

There is no information on the effect of COVAN on human fertility. Oral administration of pseudoephedrine to rats, at doses of 100 mg/kg/day in males and 20 mg/kg/day in females, did not impair fertility or alter morphological development and survival.

No studies have been conducted in animals to determine whether triprolidine or codeine have the potential to impair fertility.