Linctus Codeine Blanc Product Monograph

1 INDICATIONS

LINCTUS CODEINE BLANC is indicated for the control of exhausting, nonproductive cough which does not respond to non-opioids.

Pediatrics (<18 years of age): LINCTUS CODEINE BLANC is not indicated for use 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).

1.1 Geriatrics

Geriatrics >65 years of age: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. 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 (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

2 CONTRAINDICATIONS

LINCTUS CODEINE BLANC is contraindicated in:

• Patients who are hypersensitive to the active substance codeine phosphate or other opioid analgesics or to any ingredient in the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• 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 acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus.
• Patients with acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale.
• Patients with acute alcoholism, delirium tremens, and convulsive disorders, diabetes, heart or thyroid disease or glaucoma.
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
• CYP2D6 ultra-rapid metabolizers who convert codeine into its active metabolite more rapidly and completely than other people (see WARNINGS AND PRECAUTIONS, Risk of Death in Ultra-Rapid Metabolizers of Codeine; SYMPTOMS AND TREATMENT OF OVERDOSAGE, Codeine)
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).
• Women who are breast-feeding, pregnant or during labour and delivery (see SERIOUS WARNINGS AND PRECAUTIONS, and WARNINGS AND PRECAUTIONS).
• Pediatric patients < 12 years of age
• Pediatric patients (<18 years of age) who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings And Precautions

4 DOSAGE AND ADMINISTRATION

Pediatrics (under 18 years)

LINCTUS CODEINE BLANC is not indicated for use 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.

LINCTUS CODEINE BLANC should only be used in patients for whom alternative treatment options (e.g. non-opioid antitussive) are ineffective or not tolerated or would be otherwise inadequate to provide appropriate management of cough (see DOSAGE AND ADMINISTRATION)

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. The maximum recommended daily dose of LINCTUS CODEINE BLANC is 120 mg (18 morphine milligram equivalent). Each patient should be assessed for their risk prior to prescribing LINCTUS CODEINE BLANC, as the likelihood of experiencing serious adverse events can depend upon the type of opioid, 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 LINCTUS CODEINE BLANC.

4.1 Dosing Considerations

• LINCTUS CODEINE BLANC may be taken with or without food with a glass of water.

4.2 Recommended Dose and Dosage Adjustment

Codeine, including LINCTUS CODEINE BLANC, should be prescribed at the lowest effective dose for the shortest period of time.

Adults (18 years and older) : 5 to 10 mL every 4 to 6 hours as necessary.

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. LINCTUS CODEINE BLANC should be initiated at a low dose and slowly titrated to effect (see WARNINGS AND PRECAUTIONS)

Adjustment or Reduction of Dosage:

Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including LINCTUS CODEINE BLANC. Withdrawal (abstinence) symptoms may occur following abrupt discontinuation of 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.

4.3 Administration

LINCTUS CODEINE BLANC must be taken orally.

4.4 Missed Dose

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.

4.5 Disposal

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

LINCTUS CODEINE BLANC should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended. Unused or expired LINCTUS CODEINE BLANC 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 a lockable medication box could be obtained from a pharmacy.

5 OVERDOSAGE

5.1 Symptoms:

Euphoria, dysphoria visual disturbances, hypotension and coma or death from respiratory depression.

5.2 Treatment:

Symptomatic and supportive therapy. Maintain ventilation and administer oxygen as needed. The opioid antagonist naloxone should be administered. If the patient is conscious and has not lost the gag reflex, empty the stomach by inducing emesis with ipecac syrup. If the patient is extremely drowsy, unconscious, convulsing or has no gag reflex, perform gastric lavage. Follow with activate charcoal (50 to 100 g in adults) and a cathartic

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging.

7 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.

Codeine, including LINCTUS CODEINE BLANC 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.

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 instructed not to give LINCTUS CODEINE BLANC to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. LINCTUS CODEINE BLANC should be stored securely to avoid theft or misuse.

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

Patients should be counselled to stop use and consult a physician if symptoms or cough worsen or persist for more than 7 days, or if high fever, rash or persistent headache is present, as these could be signs of a serious condition.

Patients should be counselled to discontinue codeine products and to seek urgent medical help at the earliest sign of codeine toxicity including symptoms such as confusion, shallow breathing, or extreme sleepiness which may be life threatening.

Abuse and Misuse

Like all opioids, LINCTUS CODEINE BLANC is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, LINCTUS CODEINE BLANC 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 LINCTUS CODEINE BLANC, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse

LINCTUS CODEINE BLANC is intended for oral use only.

Cardiovascular

Codeine administration may result in hypotension and dizziness. Use with caution in patients with cardiac arrhythmias due to the cholinergic effects of the drug.

Driving and Operating Machinery

Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. LINCTUS CODEINE BLANC may 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 phosphate with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.

Dependence/Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated administration of LINCTUS CODEINE BLANC and there is a potential for development of psychological dependence.

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.

Use in Drug and Alcohol Addiction

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

Endocrine and Metabolism

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

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. Codeine should not be used in patients with diarrhea associated with pseudomembranous colitis. Use with caution in patients with acute ulcerative colitis or other severe inflammatory bowel disease due to the risk of toxic megacolon.

Constipation: LINCTUS CODEINE BLANC causes a reduction in gastrointestinal motility associated with an increase smooth muscle tone. Constipation is a frequently reported side effect of part of an opioid treatment. Patients should be advised of steps to prevent constipation and consider the prophylactic use of laxatives. Particular caution advised in patients with chronic constipation.

Gastrointestinal transit: Clinical conditions or medical products that cause sudden shortening and marked gastrointestinal transit time may lead to decreased absorption of Codeine phosphate in LINCTUS CODEINE BLANC and may cause withdrawal symptoms in patients with physical dependence on opioids.

Acute abdominal disorders: Opioid administration may overshadow the diagnosis or the clinical course of acute abdominal conditions. Therefore, it is important to make sure that the patient does not show bowel obstruction, or even Ileus, before initiating treatment.

Neonatal Opioid Withdrawal Syndrome (NOWS)

Use of LINCTUS CODEINE BLANC 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 LINCTUS CODEINE BLANC, 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 when LINCTUS CODEINE BLANC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).

Serotonin Syndrome: LINCTUS CODEINE BLANC 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 serotoninergic 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. LINCTUS CODEINE BLANC 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).

Head Injury: The respiratory depressant effects of Codeine phosphate, 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 phosphate may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, codeine phosphate must be used with extreme caution and only if it is judged essential (see CONTRAINDICATIONS).

Peri-Operative Considerations

Use with caution in sedated or debilitated patients, in patients who have undergone thoracotomies or laparotomies, since suppression of the cough reflex may lead to retention of secretions postoperatively in these patients.

Respiratory

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 phosphate 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 LINCTUS CODEINE BLANC, 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 LINCTUS CODEINE BLANC 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 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). Codeine-containing products are contraindicated for all children younger than 12 years of age

• Codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome (see CONTRAINDICATIONS).
• Avoid the use of codeine-containing products in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

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 LINCTUS CODEINE BLANC, as in these patients, even usual therapeutic doses of LINCTUS CODEINE BLANC may decrease respiratory drive to the point of apnea. The use of LINCTUS CODEINE BLANC is contraindicated in Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS).

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 labelled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. . (See also Labour, Delivery and Nursing Women in Special Populations).

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 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 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 Robitussin® AC requires careful consideration of the Page 10 of 27 effects on the parent drug, codeine, and the active metabolite, morphine. (See DRUG INTERACTIONS).

Sexual Health

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- Marketing Experience).

7.1 Special Populations

7.1.1 Pregnant Women

Pregnant Women: Studies in human have not been conducted. LINCTUS CODEINE BLANC crosses the placental barrier and is contraindicated in pregnant women and during labour and delivery. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a physician prior to initiating or continuing therapy with LINCTUS CODEINE BLANC

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, may 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 and Delivery: Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if LINCTUS CODEINE BLANC is used in this population (See WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome).

7.1.2 Breast-feeding

Since opioids can cross the placental barrier and are excreted in breast milk, LINCTUS CODEINE BLANC is contraindicated in nursing women and during labour and delivery. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opioids, should be readily available if LINCTUS CODEINE BLANC is used in this population.

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, Risk of Death in 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 breast-fed infants. 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, LINCTUS CODEINE BLANC is contraindicated in breast-feeding. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about any use of codeine during breast-feeding.

7.1.3 Pediatrics

LINCTUS CODEINE BLANC is not indicated for use 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)

7.1.4 Geriatrics

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 (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

7.1.5 Special Risk Groups

Codeine phosphate should be administered with caution to patients with a history of alcohol and drug abuse, or history of seizures, and in a reduced dosage to debilitated patients, and those with severe impairment of hepatic or renal function, and to patients with severely impaired pulmonary function, Addison’s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse effects of LINCTUS CODEINE BLANC are similar to those of other opioid antitussives and represent an extension of pharmacological effects of the drug class.

The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

Adverse reactions due to codeine phosphate may include drowsiness, nausea, vomiting and constipation. Infrequent adverse effects include palpitation, dry mouth, skin rash, pruritus and, rarely, hyperhidrosis and agitation have been reported. Respiratory depression is seen in higher dosage, and there is a potential for tolerance, psychological dependence or physical dependence to occur.

Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy.

The following adverse effects occur less frequently with opioid products and include those reported in LINCTUS CODEINE BLANC clinical trials, whether related or not to Codeine phosphate.

Cardiovascular: Supraventricular tachycardia, bradycardia, palpitations, faintness, syncope, postural hypotension and hypertension, and phlebitis following i.v. injection.

Gastrointestinal: Dry mouth, nausea, vomiting, constipation, biliary tract spasm, laryngospasm, anorexia, diarrhea, cramps, dyspepsia, taste alterations.

General and CNS: Drowsiness, sedation, euphoria, dysphoria, weakness, headache, agitation, seizures, uncoordinated muscle movements, alterations of mood, dreams, hallucinations and disorientation, visual disturbances, insomnia, miosis, toxic psychoses. Genitourinary: Urinary retention or hesitance, antidiuretic effect, reduced libido and/or potency.

Nausea and Vomiting: Occur frequently after single doses of narcotics or as an early unwanted effect of regular opioid analgesic therapy.

Other: Abnormal liver function test results (propoxyphene flushing/warmth).

8.2 Post-Market Adverse Reactions

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.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions Box

9.2 Overview

Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants: 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) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. 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). LINCTUS CODEINE BLANC should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.

Interaction with Serotonin

Coadministration of codeine phosphate 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).

9.3 Drug-Drug Interactions

Anticholinergics: Concomitant use of drugs with antimuscarinic activity may increase the risk of severe constipation and/or urinary retention.

Cimetidine: Concurrent administration of cimetidine may lead to increased effect or toxicity of opioid analgesics.

CNS Agents: Concomitant administration of other CNS drugs such as sedatives, hypnotics, phenothiazines, anesthetics and alcohol may increase the sedative and depressant effects of opioid analgesics. If the concomitant use of these drugs is considered necessary, their doses should be reduced accordingly.

MAO Inhibitors: Serious adverse reactions have been reported in patients who receive MAO inhibitors with pethidine. Other opioid analgesics should be used with extreme caution, if at all, in patients taking MAO inhibitors (including selegiline) or within 14 days of such therapy.

Opioid Antagonists: Naltrexone and agonist-antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol) should not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist-antagonists may reduce the analgesic effect or may precipitate withdrawal symptoms.

Other Opioids: The use of more than one opioid agonist at a time is usually inappropriate; additive CNS depressant, respiratory depressant and hypotensive effects may occur if 2 or more agonists are used concurrently. Potentiation of effects may occur with a previously administered long-acting opioid analgesic.

Tricyclic Antidepressants: Tricyclic antidepressants may enhance opioid-induced respiratory depression.

Warfarin: Opioid agonists may potentiate the anticoagulant effects of coumarin anticoagulants.

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 LINCTUS CODEINE BLANC 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.

CYP3A4 inhibitors: The concomitant use of LINCTUS CODEINE BLANC 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 LINCTUS CODEINE BLANC

CYP2D6 inhibitors: The concomitant use of LINCTUS CODEINE BLANC 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 inducers: The concomitant use of LINCTUS CODEINE BLANC 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 a concomitantly used CYP3A4 inducer 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.

9.4 Drug-Laboratory Test 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.

9.5 Drug-Lifestyle Interactions

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

10 ACTION AND CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Codeine exerts its effect on opiate receptors, primarily in the CNS and smooth muscle. Its effects include: analgesia, respiratory depression, suppression of the cough reflex, decreased gastrointestinal motility. CNS changes and stimulation of the chemoreceptor trigger zone which causes nausea and vomiting.

Central Nervous System: Codeine phosphate 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 phosphate 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 phosphate 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 phosphate overdose.

Gastrointestinal Tract and Other Smooth Muscle: Codeine phosphate 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 phosphate 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.

10.2 Pharmacodynamics

Codeine is well absorbed orally and from parenteral sites. Onset of analgesic action occurs in

10 to 30 minutes after parenteral administration or in up to 45 minutes following an oral dose. Peak effect is reached in 30 to 60 minutes after an i.m. or s.c. dose or 1 to 2 hours after oral dosing. Analgesia lasts 4 to 6 hours. Codeine’s antitussive effect peaks within 1 to 2 hours and lasts up to 4 hours. Its plasma half-life is approximately 3 to 4 hours but may be as long as 19 hours in anephric patients. Codeine is approximately 7% bound to plasma protein; its volume of distribution is 2.5 to 3.5 L/kg. It is primarily metabolized by the liver, and its metabolites, some active, are eliminated in the urine. Only a small fraction (0.01) is excreted unchanged.

10.3 Pharmacokinetics

Special Populations and Conditions

Pediatrics (< 18 years of age):

LINCTUS CODEINE BLANC is not indicated for use 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).

Geriatrics: Elderly patients may be more susceptible to adverse effects, especially respiratory depression and constipation. Caution is advised; the initial dose should be reduced and effects monitored. Elimination and metabolism may be slowed; lower doses or longer dosing intervals may be required.

11 STORAGE, STABILITY AND DISPOSAL

Store between 15 - 30 C.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Codeine phosphate

Chemical name: 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate hemihydrate

Molecular formula: C₁₈H₂₁NO₃,H₃PO₄,½H₂O

Molecular mass: 406.4

Structural formula:

https://www.pharmacopoeia.com/bp-2018/monographs/codeine-phosphate.html?date=2018-01-01&text=codeine+phosphate

Physicochemical properties: Hemihydrate, fine, white, needle-shaped crystals; a crystalline powder; odorless, affected by light.

Solubility: Freely soluble in water, very soluble in hot water, slightly soluble in alcohol, more soluble in boiling alcohol.