Codeine is an active pharmaceutical ingredient in the Opium Alkaloids and Derivatives group (R05DA). The information below is compiled per regulator from the product labels on record, with direct links to the original documents.
GBOfficial regulatory label· revised March 21, 2025[1]
Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by paracetamol or ibuprofen alone. Solpadeine Plus Soluble Tablets are recommended for the relief of migraine, headache, backache, rheumatic pain, period pains, dental pain, strains & sprains and sciatica.
4. CLINICAL PARTICULARS
How to take
CACanada· Health Canada
6 products
Uses
CAOfficial regulatory label· revised March 22, 2025[2]
CODEINE PHOSPHATE SYRUP is indicated for the symptomatic treatment of mild to moderate pain. 1 Pediatrics Pediatrics < 12 years of age: Regardless of clinical setting, the use of codeine is contraindicated in patients below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics; also, DOSING AND ADMINISTRATION) Pediatrics (12 - 18 years of age): The safety and efficacy of CODEINE PHOSPHATE SYRUP has not been studied in the pediatric population.
Therefore, the use of CODEINE PHOSPHATE SYRUP is not recommended in patients over 12 and under 18 years of age. 2 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).
USUnited States· FDA
1 product
Uses
USOfficial regulatory label· revised December 22, 2025[3]
1 INDICATIONS AND USAGE Codeine Sulfate Tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. 1 )] , reserve opioid analgesics, including Codeine Sulfate Tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Codeine Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. ( 1 ) Limitations of Use • Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Codeine Sulfate Tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Drug interactions
Known interactions involving Codeine. Select one for details. This list is informational and not a complete interaction checker.
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Interaction data compiled from DDInter (academic, CC-BY). Severity classification only - this is not a complete interaction checker and not medical advice.
[1]MHRA (UK) · PL028550080 · revised March 21, 2025
[2]Health Canada (DPD) · 00050024 · revised March 22, 2025
[3]FDA DailyMed · 010905f9-3bcb-4b… · revised December 22, 2025 [PDF]
Information on this page is compiled from public regulatory records. Drugvu is not affiliated with any regulator or pharmaceutical manufacturer. This is not medical advice. Always consult a qualified healthcare professional.
GBOfficial regulatory label· revised March 21, 2025[1]
Posology Adults 2 tablets dissolved in at least half a tumbler of water every 4-6 hours up to four times a day. The minimum dosing interval is 4 hours. No more than 4 doses (8 tablets) should be given in 24 hours.
Paediatric population:
Adolescents aged 16-18 years: 1-2 tablets every 6 hours up to 4 times a day. The minimum dosing interval is 6 hours. No more than 4 doses (8 tablets) should be given in 24 hours. Adolescents aged 12 – 15 years: 1 tablet every 6 hours up to 4 times a day.
The minimum dosing interval is 6 hours. No more than 4 doses (4 tablets) should be given in 24 hours. 4).
Elderly patients:
Elderly patients, especially those who are frail or immobile, may require a reduced dose or frequency of dosing.
Renal impairment:
Patients who have been diagnosed with kidney impairment must seek medical advice before taking this medication. It is recommended, when giving paracetamol to patients with renal failure, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours.
4).
Hepatic impairment:
Patients who have been diagnosed with hepatic impairment or Gilbert’s Syndrome must seek medical advice before taking this medication. 4). 9) Method of administration For oral administration only. 9). Minimum dosing interval: 4 hours for adults and 6 hours for adolescents.
The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician. 4. CLINICAL PARTICULARS
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
GBOfficial regulatory label· Adverse reactions· revised March 21, 2025[1]
Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post- marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system.
The following convention has been utilized for the classification of undesirable effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, 363 <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).
Paracetamol Body System Undesirable effect Frequency Blood and lymphatic system disorders Thrombocytopenia Agranulocytosis Not known Anaphylaxis Not known Immune system disorders Allergies (not including angioedema) Rare Metabolism and nutrition disorders High anion gap metabolic acidosis Not known Respiratory, thoracic and mediastinal disorders Bronchospasm* Not known Hepatobiliary disorders Hepatic dysfunction Not known Skin and subcutaneous tissue disorders Cutaneous hypersensitivity reactions including skin rashes, pruritus, sweating, purpura, urticaria and angioedema Very rare Very rare cases of serious skin reactions have been reported.
4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients. * There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
Caffeine Body System Undesirable effect Frequency Central nervous system Nervousness Dizziness Not known When the recommended paracetamol-caffeine-codeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.
Codeine Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class. The frequency of these reactions is not known. 4) Not known Gastrointestinal disorder Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis Not known Nervous system disorder Dizziness Hyperalgesia Drowsiness.
Not known General disorders and administration Drug withdrawal syndrome Uncommon Renal and urinary disorders Difficulty with micturition Not known Skin and subcutaneous tissue disorder Pruritus, sweating Not known Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. 4. CLINICAL PARTICULARS
GBOfficial regulatory label· Warnings and precautions· revised March 21, 2025[1]
Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with non- cirrhotic alcoholic liver disease. g. chronic alcoholism), who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin.
If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
Care should be observed in administering the product to any patient, whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy, hypothyroidism and those with inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis.
Care should also be observed if prolonged therapy is contemplated. Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued.
The diagnosis of medication overuse headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications. Precaution should be observed in patients with asthma who are sensitive to acetylsalicylic acid since mild bronchospasms are reported in association with paracetamol (cross reaction).
Do not exceed the stated dose. Patients should be advised not to take other paracetamol or codeine- containing products concurrently. 9). If symptoms persist for more than 3 days or get worse, or if any other symptoms occur, treatment should be discontinued, and a physician consulted.
Patients with obstructive bowel disorders or acute abdominal conditions should consult a doctor before using this product. Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients.
g. 9). 5) should not take this product. Codeine, as with other opioids should be used with caution in patients with hypotension, hypothyroidism, head injury or raised intracranial pressure. This medicinal product contains 427 mg sodium per Soluble Tablet, equivalent to 22% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
GBOfficial regulatory label· Contraindications· revised March 21, 2025[1]
Solpadeine Plus Soluble Tablets are contraindicated in patients with hypersensitivity to paracetamol, caffeine, codeine, opioid analgesics or any of the other constituents. 6). In respiratory depression, chronic constipation. In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.
This is not medical advice. Consult a qualified healthcare professional.
CAOfficial regulatory label· revised March 22, 2025[2]
, non-opioid analgesics) or would be otherwise inadequate to provide appropriate management of pain (see DOSAGE AND ADMINISTRATION) For acute pain, it is recommended that CODEINE PHOSPHATE SYRUP be used for a maximum of 7 days at the lowest dose that provides adequate pain relief.
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 CODEINE PHOSPHATE SYRUP is 480 mg (72 morphine milligram equivalent). Each patient should be assessed for their risk prior to prescribing CODEINE PHOSPHATE SYRUP, as the likelihood of experiencing serious adverse events can depend upon the type of opioid, duration of treatment, level of pain as well as the patient’s own level of tolerance.
In addition, the level of pain should be assessed routinely to confirm the most appropriate dose and the need for further use of CODEINE PHOSPHATE SYRUP (see DOSAGE AND ADMINISTRATION - Adjustment or reduction of Dosage). 1 Dosing Considerations CODEINE PHOSPHATE SYRUP should be used with caution within 12 hours pre- operatively and within the first 12-24 hours post-operatively (see WARNINGS AND PRECAUTIONS, Peri-operative Considerations).
CODEINE PHOSPHATE SYRUP is not indicated for rectal administration. CODEINE PHOSPHATE SYRUP may be taken with or without food with a glass of water. The dose initiation should follow a conservative approach in certain patients such as the CODEINE PHOSPHATE SYRUP 5 mg/mL Page 7 of 31 debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture.
2 Recommended Dose and Dosage Adjustment Individual dosing requirements vary considerably based on each patient's age, weight, severity of pain, and medical and analgesic history. Codeine, including CODEINE PHOSPHATE SYRUP, should be prescribed at the lowest effective dose for the shortest period of time.
Adults: 3 to 12 mL every 3 to 6 hours as necessary.
Children under 12 years of age:
Codeine is contraindicated in children less than 12 years old because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see INDICATIONS) (see CONTRAINDICATIONS).
Patients Not Receiving Opioids at the Time of Initiation of Codeine Treatment:
The usual initial adult dose is 15 to 30 mg, orally, every 4 to 6 hours as necessary.
Patients Currently Receiving Opioids:
For patients who are currently receiving other opioids, please refer to the following table to determine the approximate analgesic equivalences of various opioid analgesics. Conversion ratios for opioids are subject to variations in kinetics governed by genetics and other factors.
When switching from one opioid to another, consider reducing the calculated dose by 25-50% to minimize the risk of overdose. Subsequently, up-titrate the dose, as required, to reach the appropriate maintenance dose. 2 6 *** Methadone Morphine dose equivalence is not reliably established *** The maximum recommended daily dose of tramadol is 300 mg - 400 mg depending on the formulation.
Busse J. The 2017 Canadian guideline for opioids for chronic non-cancer pain.
Hamilton (ON):
McMaster University; 2017 CODEINE PHOSPHATE SYRUP 5 mg/mL Page 8 of 31 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.
CODEINE PHOSPHATE SYRUP should be initiated at a low dose and slowly titrated to effect (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).
Use with Non-Opioid Medications:
If a non-opioid analgesic is being provided, it may be continued. If the non-opioid is discontinued, consideration should be given to increasing the opioid dose to compensate for the non-opioid analgesic. CODEINE PHOSPHATE SYRUP can be safely used concomitantly with usual doses of other non-opioid analgesics.
Dose Titration:
Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual's pain should aim at administration of the lowest dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.
Dosage adjustments should be based on the patient's clinical response.
Adjustment or Reduction of Dosage:
Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including CODEINE PHOSPHATE SYRUP. 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.
Following successful relief of moderate to severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient’s condition or mental state.
Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for […]
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
CAOfficial regulatory label· Adverse reactions· revised March 22, 2025[2]
1 Adverse Reaction Overview Adverse effects of CODEINE PHOSPHATE SYRUP are similar to those of other opioid analgesics, 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.
The most frequently observed adverse effects of CODEINE PHOSPHATE SYRUP are:
Sedation, nausea and vomiting, constipation and sweating. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated if the patient lies down.
Sedation:
Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance.
If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure.
If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.
Nausea and Vomiting:
Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics.
When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and CODEINE PHOSPHATE SYRUP 5 mg/mL Page 18 of 31 concurrent use of drugs with emetogenic properties.
Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
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.
Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.
The following adverse effects occur less frequently with opioid analgesics and include those reported in CODEINE PHOSPHATE SYRUP clinical trials, whether related or not to Codeine phosphate. v. injection.
Urinary retention or hesitance, antidiuretic effect, reduced libido and/or potency.
Respiratory:
Codeine, including CODEINE PHOSPHATE SYRUP 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.
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 physiologic complications, and that appropriate therapy for the primary disease is provided.
Use with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve and patients with preexisting respiratory depression, hypoxia or hypercapnia.
Usual therapeutic doses may decrease respiratory drive while simultaneously, increasing airway resistance to the point of apnea. In patients with asthma or pulmonary emphysema, codeine may, due to its drying action on the respiratory mucusa, increase viscosity of bronchial secretions and suppress the cough reflex.
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. The respiratory depressant effects of codeine and its capacity to elevate cerebrospinal fluid CODEINE PHOSPHATE SYRUP 5 mg/mL Page 19 of 31 pressure may be markedly exaggerated in the presence of head injury or intracranial lesions or pre-existing increase in intracranial pressure.
Opioids produce adverse […]
CAOfficial regulatory label· Warnings and precautions· revised March 22, 2025[2]
). Interaction with Alcohol The co-ingestion of alcohol with CODEINE PHOSPHATE SYRUP should be avoided as it may result in dangerous additive effects, causing serious injury or death (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS AND PRECAUTIONS, Neurologic and DRUG INTERACTIONS).
Reserve concomitant prescribing of CODEINE PHOSPHATE SYRUP and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation. , non-opioid analgesics) or would be otherwise inadequate to provide appropriate management of pain (see DOSAGE AND ADMINISTRATION) For acute pain, it is recommended that CODEINE PHOSPHATE SYRUP be used for a maximum of 7 days at the lowest dose that provides adequate pain relief.
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 CODEINE PHOSPHATE SYRUP is 480 mg (72 morphine milligram equivalent). Each patient should be assessed for their risk prior to prescribing CODEINE PHOSPHATE SYRUP, as the likelihood of experiencing serious adverse events can depend upon the type of opioid, duration of treatment, level of pain as well as the patient’s own level of tolerance.
In addition, the level of pain should be assessed routinely to confirm the most appropriate dose and the need for further use of CODEINE PHOSPHATE SYRUP (see DOSAGE AND ADMINISTRATION - Adjustment or reduction of Dosage). 1 Dosing Considerations CODEINE PHOSPHATE SYRUP should be used with caution within 12 hours pre- operatively and within the first 12-24 hours post-operatively (see WARNINGS AND PRECAUTIONS, Peri-operative Considerations).
CODEINE PHOSPHATE SYRUP is not indicated for rectal administration. CODEINE PHOSPHATE SYRUP may be taken with or without food with a glass of water. The dose initiation should follow a conservative approach in certain patients such as the CODEINE PHOSPHATE SYRUP 5 mg/mL Page 7 of 31 debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
CAOfficial regulatory label· Contraindications· revised March 22, 2025[2]
CODEINE PHOSPHATE SYRUP is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
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. , ileus of any type).
, acute appendicitis or pancreatitis). Patients with mild pain that can be managed with other pain medications. 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. CODEINE PHOSPHATE SYRUP 5 mg/mL Page 5 of 31 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
This is not medical advice. Consult a qualified healthcare professional.
1 )
How to take
USOfficial regulatory label· revised December 22, 2025[3]
2 DOSAGE AND ADMINISTRATION • Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. 1 ) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals.
Reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. , the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.
Clinical guidelines on opioid prescribing for some acute pain conditions are available. 1 ) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.
1 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments.
2 ) • Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Codeine Sulfate Tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose.
3 ) • Initiate treatment with 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets.
3 ) • Periodically reassess patients receiving Codeine Sulfate Tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse.
4 ) • Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
1 Important Dosage and Administration Instructions • Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] .
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
, the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 1 )] . • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets.
Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. , naloxone, nalmefene). , concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.
3 )]. 2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent .
3 Initial Dosage Initiating Treatment with Codeine Sulfate Tablets: Initiate treatment with Codeine Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia.
Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets. Adult doses of Codeine Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions.
The maximum 24-hour dose is 360 mg.
Conversion from Other Opioids to Codeine Sulfate Tablets:
There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Codeine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Codeine Sulfate Tablets dosage than to overestimate the 24-hour Codeine Sulfate Tablets dosage and manage an adverse reaction due to overdose.
4 Titration and Maintenance of Therapy Individually titrate Codeine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. 16 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Codeine Sulfate Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] .
Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 5 Safe Reduction or Discontinuation of Codeine Sulfate Tablets Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in patients who may be physically dependent on opioids.
Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.
Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Codeine Sulfate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Codeine Sulfate Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient.
It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder.
Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients.
Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. , no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks.
Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge.
Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper.
3 )].
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
USOfficial regulatory label· Adverse reactions· revised December 22, 2025[3]
16 )] The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions with codeine administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.
Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis. Other less frequently observed adverse reactions expected from opioid analgesics, including Codeine Sulfate Tablets, include: Cardiovascular System : faintness, flushing, hypotension, palpitations, syncope Digestive System : abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis Nervous System : anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness Skin and Appendages : rash, sweating, urticaria Serotonin Syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal Insufficiency :
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis :
Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Tablets. 2 )] . 8 )] .
Hypoglycemia :
Cases of hypoglycemia have been reported in patients taking opioids. , diabetes). 14 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.
Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).
Those included also had no dispensing of the qualifying opioids in the previous 6 months. 2 ) ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).
Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.
Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. 5% to 4% across study sites, counting only the first event during follow-up.
Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.
Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.
The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. gov/medwatch.
USOfficial regulatory label· Warnings and precautions· revised December 22, 2025[3]
5 WARNINGS AND PRECAUTIONS • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
8 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. 9 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
11 ) • Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of Codeine Sulfate Tablets in patients with circulatory shock. 12 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression.
Avoid use of Codeine Sulfate Tablets in patients with impaired consciousness or coma. 1 Addiction, Abuse, and Misuse Codeine Sulfate Tablets contain codeine, a Schedule II controlled substance. As an opioid, Codeine Sulfate Tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Codeine Sulfate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy.
In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Codeine Sulfate Tablets, and reassess all patients receiving Codeine Sulfate Tablets for the development of these behaviors and conditions.
, major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Codeine Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Codeine Sulfate Tablets along with frequent reevaluation for signs of addiction, abuse, and misuse.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
USOfficial regulatory label· Contraindications· revised December 22, 2025[3]
6 )] . 6 )] . 2 )]. 9 )]. 10 ), Drug Interactions ( 7 )]. 14 )]. , anaphylaxis) [see Adverse Reactions ( 6 )] . • Children younger than 12 years of age. • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
( 4 ) • Significant respiratory depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Hypersensitivity to codeine. ( 4 )
This is not medical advice. Consult a qualified healthcare professional.
The maximum daily dose of this product is equivalent to 171% of the WHO recommended maximum daily intake for sodium. Solpadeine Plus Soluble Tablets is considered high in sodium. This should be particularly taken into account for those on a low salt diet.
This medicine contains 50 mg sorbitol in each soluble tablet Sorbitol is a source of fructose. If your doctor has told you that you (or your child) have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you (or your child) take or receive this medicine.
CYP2D6 metabolism:
Codeine is metabolized by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency.
However, if the patient is an extensive or ultra-rapid metabolizer there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher-than-expected serum morphine levels.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.
3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive […]
2 Recommended Dose and Dosage Adjustment Individual dosing requirements vary considerably based on each patient's age, weight, severity of pain, and medical and analgesic history. Codeine, including CODEINE PHOSPHATE SYRUP, should be prescribed at the lowest effective dose for the shortest period of time.
Adults: 3 to 12 mL every 3 to 6 hours as necessary.
Children under 12 years of age:
Codeine is contraindicated in children less than 12 years old because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see INDICATIONS) (see CONTRAINDICATIONS).
Patients Not Receiving Opioids at the Time of Initiation of Codeine Treatment:
The usual initial adult dose is 15 to 30 mg, orally, every 4 to 6 hours as necessary.
Patients Currently Receiving Opioids:
For patients who are currently receiving other opioids, please refer to the following table to determine the approximate analgesic equivalences of various opioid analgesics. Conversion ratios for opioids are subject to variations in kinetics governed by genetics and other factors.
When switching from one opioid to another, consider reducing the calculated dose by 25-50% to minimize the risk of overdose. Subsequently, up-titrate the dose, as required, to reach the appropriate maintenance dose. 2 6 *** Methadone Morphine dose equivalence is not reliably established *** The maximum recommended daily dose of tramadol is 300 mg - 400 mg depending on the formulation.
Busse J. The 2017 Canadian guideline for opioids for chronic non-cancer pain.
Hamilton (ON):
McMaster University; 2017 CODEINE PHOSPHATE SYRUP 5 mg/mL Page 8 of 31 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.
CODEINE PHOSPHATE SYRUP should be initiated at a low dose and slowly titrated to effect (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).
Use with Non-Opioid Medications:
If a non-opioid analgesic is being provided, it may be continued. If the non-opioid is discontinued, consideration should be given to increasing the opioid dose to compensate for the non-opioid analgesic. CODEINE PHOSPHATE SYRUP can be safely used concomitantly with usual doses of other non-opioid analgesics.
Dose Titration:
Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual's pain should aim at administration of the lowest dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.
Dosage adjustments should be based on the patient's clinical response. […]
2 )]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Codeine Sulfate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug.
Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.
Respiratory depression, 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 overdose reversal agents , depending on the patient’s clinical status [see Overdosage ( 10 )].
Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Codeine Sulfate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase.
4 )]. Overestimating the Codeine Sulfate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Codeine Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.
Opioid use increases the risk of CSA in a dose-dependent fashion. 4 )]. , naloxone, nalmefene). , concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.
3 )] . , prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics.
Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.
3 ), Overdosage ( 10 )] . , non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] .
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.
If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
2 ), Overdosage ( 10 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when Codeine Sulfate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 )] .
4 Neonatal Opioid Withdrawal Syndrome Use of Codeine Sulfate Tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. 1 )] . 5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.
Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. com. gov\OpioidAnalgesicREMSBlueprint. 6 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine.
Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression.
For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect.
Because of the risk of life-threatening respiratory depression and death: • Codeine Sulfate Tablets are contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )]. • Codeine Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )].
• Avoid the use of Codeine Sulfate Tablets 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.
4 ), Overdosage ( 10 )].
Nursing Mothers:
At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. 2 )] . , gene duplications denoted as *1/*1xN or *1/*2xN). , Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).
These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage ( 10 )].
Therefore, individuals who are ultra-rapid metabolizers should not use Codeine Sulfate Tablets. 7 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 Codeine Sulfate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. , ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
The concomitant use of Codeine Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels.
This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Regularly evaluate patients receiving Codeine Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Tablets are used in conjunction with inhibitors and inducers of CYP3A4.
If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Codeine Sulfate Tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation.
If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Codeine Sulfate Tablets dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of opioid withdrawal [Drug Interactions ( 7 )] .
, amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.
Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
Regularly evaluate patients receiving Codeine Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Tablets are used in conjunction with inhibitors of CYP2D6.
If concomitant use with a CYP2D6 inhibitor is necessary, evaluate the patient at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the Codeine Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Codeine Sulfate Tablets dosage and evaluate the patient at frequent intervals for signs and symptoms of respiratory depression or sedation [see Drug Interactions ( 7 )] .
8 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. 3 )] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).
These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.
Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. 16 ] . 9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Codeine Sulfate Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
2 )] . 2 )] . 3 ), Drug Interactions ( 7 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 10 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion.
Codeine Sulfate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions ( 7 )] . 11 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.
12 Severe Hypotension Codeine Sulfate Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. , phenothiazines or general anesthetics) [see Drug Interactions ( 7 )]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Codeine Sulfate Tablets.
In patients with circulatory shock, Codeine Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Codeine Sulfate Tablets in patients with circulatory shock. , those with evidence of increased intracranial pressure or brain tumors), Codeine Sulfate Tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure.
Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Codeine Sulfate Tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Codeine Sulfate Tablets in patients with impaired consciousness or coma.
14 Risks of Gastrointestinal Complications Codeine Sulfate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in Codeine Sulfate Tablets may cause spasm of the sphincter of Oddi.
Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids.
The risk of OIED may increase as the dose and/or duration of opioids increases. 2 )] . 15 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Codeine Sulfate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.
Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Codeine Sulfate Tablets therapy. 16 Withdrawal Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in a patient physically dependent on opioids.
When discontinuing Codeine Sulfate Tablets in a physically-dependent patient, gradually taper the dosage. 3 )]. , buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Codeine Sulfate Tablets.
In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 17 Risks of Driving and Operating Machinery Codeine Sulfate Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Codeine Sulfate Tablets and know how they will react to the medication.