Codeine phosphate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CODEINE PHOSPHATE (CODEINE PHOSPHATE)

Composition:

Active substance: codeine phosphate;

One tablet contains 30 mg of codeine phosphate hemihydrate (equivalent to 22.1 mg of codeine base);

Excipients: lactose monohydrate, potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, flat cylindrical tablets with beveled edges; the trade mark of the manufacturer is imprinted on one side of the tablet, a score line is present on the other side for division.

Pharmacotherapeutic group.

Opium alkaloids and derivatives. Codeine. ATC code R05D A04.

Pharmacological Properties.

Pharmacodynamics.

Codeine is an analgesic agent with effects similar to those of morphine, but with significantly weaker analgesic activity and a milder sedative effect. Codeine is a weak central-acting analgesic. Codeine exerts its effects by interacting with μ-opioid receptors, although it has low affinity for these receptors. The analgesic effect of codeine is due to its conversion into morphine. It has been shown that codeine, particularly in combination with other analgesics such as paracetamol, is effective in the treatment of acute nociceptive pain.

Codeine is also used as an antitussive and antidiarrheal agent.

Pharmacokinetics.

Codeine and its salts are rapidly absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration of codeine is reached within 1 hour. The plasma half-life is 3–4 hours. The ratio of analgesic potency after oral administration versus intramuscular injection is approximately 1:1.5. Codeine is metabolized in the liver by O- and N-demethylation to form morphine and norcodeine. Codeine and its metabolites are excreted by the kidneys, primarily as glucuronide conjugates. Most of the excreted products are eliminated in urine within 6 hours, and up to 86% of the dose is excreted from the body within 24 hours. Approximately 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine, and another 10% as free or conjugated norcodeine. Only trace amounts of excretory products are found in feces.

Clinical Characteristics.

Indications.

Pain of mild to moderate intensity that is not relieved by other analgesics such as paracetamol or ibuprofen.

Dry or painful cough.

Diarrhea.

Contraindications.

Hypersensitivity to codeine or other opioid analgesics, or to any component of the drug; acute respiratory depression; obstructive respiratory tract diseases; bronchial asthma (opioids should not be used during an asthma attack); liver disease, severe impairment of liver function; alcohol intoxication; head injuries or conditions associated with increased intracranial pressure (in addition to the risk of respiratory depression and elevated intracranial pressure, codeine may affect pupillary response and other vital signs during neurological status assessment); conditions where inhibition of peristalsis should be avoided or conditions associated with abdominal distension; risk of paralytic ileus; acute diarrheal conditions such as acute ulcerative colitis or antibiotic-associated colitis (e.g., pseudomembranous colitis), or diarrhea caused by poisoning.

The drug is contraindicated in the following patient groups:

children under 12 years of age;

children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea;

children aged 12 to 18 years with compromised respiratory function;

pregnant or breastfeeding women;

patients of any age who are ultra-rapid/extensive metabolizers via CYP2D6.

Interaction with other medicinal products and other forms of interactions.

Alcohol: possible enhancement of hypotensive and sedative effects of alcohol, as well as increased respiratory depression caused by alcohol.

Anesthetics, sodium oxybate: possible enhancement of CNS depression and/or respiratory depression and/or hypotension.

Antidepressants: tricyclic antidepressants may enhance the depressant effects of opioid analgesics.

Concomitant use of monoamine oxidase inhibitors (MAOIs) with meperidine has been associated with severe CNS excitation/depression (including hypertension or hypotension). Although such an interaction has not been documented with codeine, a similar interaction cannot be excluded. Therefore, codeine should not be used concomitantly with MAO inhibitors or within 2 weeks after discontinuation of their use.

Neuroleptics: enhanced sedative and hypotensive effects.

Anxiolytics and hypnotics: enhanced sedative effect, increased risk of respiratory depression.

Antihistamines: concomitant use of codeine and antihistamines with sedative properties may lead to enhanced CNS depression and/or respiratory depression and/or hypotension.

Antihypertensive agents: enhanced hypotensive effect.

Anticholinergics (e.g., atropine): risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention.

Antiarrhythmic agents: codeine slows the absorption of mexiletine. When codeine is used concomitantly with quinidine, the analgesic effect of codeine is likely to be significantly reduced due to the negative effect of quinidine on its metabolism.

Domperidone, metoclopramide: codeine antagonizes the effects of cisapride, metoclopramide, and domperidone on gastrointestinal motility.

Antidiarrheal agents: increased risk of severe constipation.

Opioid antagonists (e.g., buprenorphine, naltrexone, naloxone): possible precipitation of withdrawal syndrome.

Cyprofloxacin: opioid premedication should be avoided, as opioids reduce plasma concentrations of cyprofloxacin.

Ritonavir: possible increase in plasma levels of opioid analgesics (particularly codeine).

Mexiletine: absorption of mexiletine is slowed when used concomitantly with codeine.

Antiulcer drugs: cimetidine may inhibit the metabolism of codeine, leading to increased plasma concentration.

Effect on instrumental examinations: opioid use may interfere with the assessment of gastric emptying, as opioids delay gastric emptying, and also with hepatobiliary imaging using Technetium Tc 99m Disofenin, since opioid therapy may cause Oddi sphincter constriction and increased biliary tract pressure.

Special precautions for use.

Codeine is not recommended for use in patients with acute asthma. Codeine should be used with caution or require dose reduction when treating asthma and reduced respiratory reserve. The use of codeine should be avoided during acute asthma attacks (see section "Contraindications"). Codeine should be used with caution in patients with impaired renal or hepatic function, biliary tract disorders (including gallstone disease), history of drug abuse, respiratory dysfunction, and history of asthma. The dose of codeine should be reduced in elderly patients, debilitated patients, patients with hypotension, hypothyroidism, prostate hypertrophy, adrenal insufficiency (e.g., Addison's disease), inflammatory or obstructive gastrointestinal disorders (codeine reduces peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon) (see section "Contraindications"), urethral stricture, shock, seizure disorders, and myasthenia gravis. The dose of codeine should be reduced in patients with renal insufficiency. Codeine should be used with caution in patients who have recently undergone surgery on the gastrointestinal tract (due to possible decreased gastrointestinal motility) or urinary tract (such patients are more prone to urinary retention caused directly by urethral sphincter spasm and constipation due to codeine use). Codeine should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release). Discontinuation of treatment should be done gradually in patients who may have physical dependence in order to avoid precipitating withdrawal symptoms.

CYP2D6 metabolism

Codeine is converted to its active metabolite – morphine – in the liver by the enzyme CYP2D6. If a patient has a deficiency of this enzyme or if CYP2D6 is completely absent, adequate analgesic effect will not be achieved. Estimates indicate that up to 7% of the Caucasian population may have this CYP2D6 metabolic characteristic. However, if a patient is an ultra-rapid or extensive metabolizer via CYP2D6, there is an increased risk of developing adverse effects – symptoms of opioid toxicity – even with usual doses. In such patients, the conversion of codeine to morphine rapidly leads to higher serum morphine levels than expected.

General symptoms of opioid toxicity: confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, loss of appetite. In severe cases, symptoms of circulatory and respiratory depression may occur, which can be life-threatening and very rarely fatal.

Data on the prevalence of ultra-rapid metabolizers via CYP2D6 in different populations are provided below:

Population	Prevalence, %
Africans/Ethiopians	29
African Americans	3.4–6.5
Mongoloids	1.2–2
Caucasians	3.6–6.5
Greeks	6
Hungarians	1.9
North Europeans	1–2

Postoperative use in children

There are reports in the published literature that the use of codeine in children after tonsillectomy and/or adenoidectomy for prevention of obstructive sleep apnea led to rare but life-threatening adverse reactions, including fatal outcomes. All children received codeine doses within the recommended dosage range. However, evidence suggests that these children were either ultra-rapid or extensive metabolizers of codeine.

Children with compromised respiratory function

Codeine is not recommended for use in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple trauma, or major surgical procedures. These factors may exacerbate symptoms of morphine toxicity.

Opioid analgesics should be avoided or used with caution in patients with biliary tract disorders, or should be administered in combination with spasmolytics.

The use of meperidine and possibly other opioid analgesics in patients taking monoamine oxidase inhibitors (MAOIs) may be associated with severe reactions, sometimes resulting in fatal outcomes. If the use of codeine in patients receiving MAOIs is essential, codeine should be administered with extreme caution, or MAOI therapy should be discontinued at least 14 days prior to initiating codeine treatment (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol consumption should be avoided during treatment with codeine.

Opioid analgesics reduce salivary secretion, which may lead to the development of dental caries and oral mucosal candidiasis.

In elderly patients, metabolism and elimination of codeine may be slower (see section "Method of administration and dosage").

The use of codeine requires regular physician assessment of the benefit-risk ratio.

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

The use of this medicinal product during pregnancy is contraindicated.

There have been reports of a possible association between congenital respiratory and cardiac malformations in infants and codeine use during the first trimester of pregnancy. Chronic use of codeine during pregnancy may lead to physical dependence in the fetus, resulting in neonatal withdrawal symptoms. The use of codeine during labor may depress respiration in the newborn. Opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

If use of the medicinal product is necessary, breastfeeding should be discontinued.

When used at normal therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, which are unlikely to have a negative effect on the infant. However, if the patient is an ultra-rapid metabolizer via CYP2D6, higher levels of morphine may accumulate in breast milk, and in very rare cases this may lead to potentially fatal opioid toxicity symptoms in the infant.

Ability to influence reaction speed when driving or operating machinery.

During treatment with this medicinal product, patients should refrain from driving or operating machinery due to the possible occurrence of effects such as confusion, drowsiness, dizziness, hallucinations, visual disturbances, or seizures. The effects of alcohol are potentiated by opioid analgesics.

Method of Administration and Dosage

For oral use.

Prolonged use of the medicinal product requires regular assessment by a physician of the benefit/risk ratio.

The drug should be used for as short a period as possible at the lowest effective dose. This dose may be taken up to 4 times daily at equal intervals. The maximum daily dose of codeine must not exceed 240 mg.

Pain of mild to moderate intensity

Adults

The recommended dose is 30–60 mg every 4 hours. The maximum daily dose is 240 mg. Further dose escalation beyond the recommended dose does not lead to a significant increase in analgesic effect.

Children aged 12 to 18 years

The recommended dose is 30–60 mg every 6 hours. The maximum daily dose is 240 mg. The dose depends on body weight (0.5–1 mg/kg).

Codeine must not be used in children aged 12 to 18 years who are undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea (see sections "Contraindications", "Special Warnings and Precautions for Use", "Children").

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function (see sections "Contraindications", "Special Warnings and Precautions for Use", "Children").

Children under 12 years of age

Not recommended (see sections "Contraindications", "Children").

Elderly patients

Dosage reduction is required.

Cough

Adults and children aged 12 to 18 years

The recommended dose is 15–30 mg 3–4 times daily.

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function (see sections "Contraindications", "Special Warnings and Precautions for Use", "Children").

Children under 12 years of age

Not recommended (see sections "Contraindications", "Children").

Elderly patients

Dosage reduction is required.

Diarrhea

Adults and children aged 12 years and older

The recommended dose is 30 mg 3–4 times daily (range: 15–60 mg).

Children under 12 years of age

Not recommended (see sections "Contraindications", "Children").

Elderly patients

Dosage reduction is required.

Children

Codeine is contraindicated in children under 12 years of age due to the risk of developing serious and life-threatening adverse reactions resulting from the variable and unpredictable metabolism of codeine to morphine in this age group (see section "Contraindications").

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea, due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions for Use").

Codeine must not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions for Use").

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid/extensive metabolizers via CYP2D6 (see sections "Contraindications", "Special Warnings and Precautions for Use").

Overdose

Overdose effects are potentiated by concomitant intake of alcohol and psychoactive substances.

Symptoms: Development of central nervous system depression, particularly respiratory depression, more frequently when used concomitantly with other sedative agents (e.g., alcohol) or in cases of overdose. Marked pupillary constriction, dry mouth, increased sweating, facial flushing, nausea and vomiting are common. Arterial hypotension and tachycardia may occur but are less likely. High doses of codeine may cause sedation or emotional excitement; in children, seizures may occur.

Treatment: General symptomatic and supportive measures, including measures to support the respiratory center and monitoring of vital signs until the patient's condition stabilizes.

Administration of activated charcoal is advisable if less than 1 hour has passed since ingestion of codeine in adults at doses exceeding 350 mg, or in children at doses exceeding 5 mg/kg body weight. Naloxone should be administered in cases of coma or respiratory depression. Naloxone is a competitive antagonist with a short elimination half-life; therefore, repeated administration of high doses may be required in patients with severe poisoning. The patient should be observed for at least 4 hours after naloxone administration, or for 8 hours if a prolonged-release naloxone formulation is used.

Adverse reactions.

Prolonged regular use of codeine is known to lead to the development of dependence and tolerance, as well as to cause restlessness and irritability after discontinuation of treatment.

At therapeutic doses, codeine causes significantly fewer adverse reactions compared to morphine.

Long-term use of codeine for headache treatment may lead to worsening of headache.

Tolerance and some of the most common side effects—drowsiness, nausea, vomiting, and confusion—typically develop with prolonged use of codeine.

Immune system disorders: maculopapular rash is considered a symptom of hypersensitivity syndrome associated with oral administration of codeine; fever, splenomegaly and lymphadenopathy, dyspnea.

Psychiatric disorders: depression, hallucinations, nightmares, restlessness, confusion, sudden mood swings, euphoria, dysphoria.

Nervous system disorders: drowsiness, dizziness, seizures (especially in infants and children), headache, increased intracranial pressure, development of tolerance or dependence.

Eye disorders: miosis, blurred vision, photophobia, visual disturbances (including blurred vision, double vision).

Ear and labyrinth disorders: dizziness.

Cardiovascular disorders: tachycardia, bradycardia, palpitations, orthostatic hypotension, facial flushing, arterial hypotension (with large doses).

Respiratory system disorders: dyspnea, respiratory depression (with large doses).

Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth, stomach spasms, pancreatitis.

Hepatobiliary disorders: biliary spasm, which may be associated with changes in liver enzyme levels.

Endocrine disorders: hyperglycemia.

Metabolism and nutrition disorders: anorexia.

Skin and subcutaneous tissue disorders: allergic reactions such as rash, urticaria, pruritus, increased sweating, facial swelling.

Musculoskeletal system disorders: uncontrolled muscle movements, muscle rigidity (with large doses).

Renal and urinary disorders: ureteral spasm, dysuria, urinary retention, difficulty in urination, antidiuretic effect.

Reproductive system disorders: sexual dysfunction, erectile dysfunction, decreased libido and potency.

General disorders: malaise, increased fatigue, hypothermia.

Withdrawal syndrome: abrupt discontinuation of codeine treatment may cause withdrawal syndrome. Possible symptoms include: tremor, insomnia, restlessness, irritability, anxiety, depression, loss of appetite, nausea, vomiting, diarrhea, excessive sweating, lacrimation, rhinorrhea, sneezing, yawning, piloerection, mydriasis, weakness, fever, muscle cramps, dehydration, increased heart rate, respiratory rate, and blood pressure.

It should be remembered that tolerance decreases rapidly after cessation of codeine use; therefore, re-administration of a previously tolerated dose may be fatal.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1 blister per carton.

Prescription category.

Prescription only.

Manufacturer.

"INTERSIM" Limited Liability Company.

Manufacturer's address.

40-A, 21st km of Staryokyivska Road, Odesa, 65025, Ukraine.