NEO-CODION ENFANT

The relief of pain (analgesia) is a primary goal for enhancing the quality of life of patients and for increasing the ability of patients to engage in day to day activities.

Codeine, an opioid analgesic, was originally approved in the US in and is a drug used to decrease pain by increasing the threshold for pain without impairing consciousness or altering other sensory functions.

Opiates such as codeine are derived from the poppy plant, Papaver somniferum (Papaveraceae).

Codeine is utilized as a central analgesic, sedative, hypnotic, antinociceptive, and antiperistaltic agent, and is also recommended in certain diseases with incessant coughing.

Codeine sulfate is a form of this drug that is commonly used.

It is available in tablet form

Label and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate Label.

The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged and above 14, 15.

General effects

Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone.

A small amount of ingested codeine is converted to morphine in the body.

Codeine increases tolerance to pain, reducing existing discomfort.

In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression 4.

Antitussive activity

This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing 4.

Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla 18.

Effects on intestinal motility

Codeine may reduce intestinal motility through both a local and possibly central mechanism of action 19.

This may possibly lead to constipation 18.

The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility Label.

Effects on the central nervous system

Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic.

Its primary site of action is at the mu opioid receptors distributed throughout the central nervous system.

The sedative activities of codeine are less potent than those of morphine 18.

Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system 8.

Effects on blood pressure

This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms Label.

Effects on chronic cancer pain and other types of pain Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties.

Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system.

The average duration of action is about 4 hours 18.

Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms 4, 7.

Mu-type opioid receptor Agonist Regulator Kappa-type opioid receptor Agonist Delta-type opioid receptor Agonist.

Codeine is absorbed from the gastrointestinal tract.

The maximum plasma concentration occurs 60 minutes after administration Label.

When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine Label.

Steady-state concentration

The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3 G) and morphine-6-glucuronide (M6 G) within 48 hours Label.

Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues Label.

Approximately 70-80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6­ glucuronide (C6 G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively.

UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide.

P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to norcodeine.

Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid.

The glucuronide metabolites of morphine are morphine-3-glucuronide (M3 G) and morphine-6-glucuronide (M6 G).

Morphine and

M6 G have been proven to have analgesic activity in humans.

The analgesic activity of

C6 G in humans is not known at this time.

Norcodeine and

M3 G are generally not considered to have analgesic properties Label.

Hover over products below to view reaction partners Codeine norcodeine Codeine-6-glucuronide Morphine morphine 3 glucuronide + morphine 6 glucuronide.

About 90% of the total dose of codeine is excreted by the kidneys.

Approximately 10% of the drug excreted by the kidneys is unchanged codeine Label.

The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5-15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine 18.

Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours Label.

Renal clearance of codeine was 183 +/.

• 59 ml min-1 in a clinical study 5.

Renal impairment may decrease codeine clearance

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LD50: 427 mg kg-1 (rat) MSDS.

Overdose/toxicity Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite.

In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal 13, Label.

Teratogenic effects This drug is classified as a pregnancy Category C drug.

There are no adequate and well-controlled studies completed in pregnant women.

Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus Label.

Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose Label.

Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification.

Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison Label.

Nonteratogenic effects

Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery.

Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding.

These signs may be observed shortly following birth and may require specific treatment Label.

Codeine (30 mg/kg) given Subcutaneous to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth.

The dose given was 0.8 times the maximum recommended human dose of 360 mg/day Label.

The use in breastfeeding/nursing Codeine is secreted into human milk.

The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants Label.

• All children younger than 12 years of age.

• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

• Significant respiratory depression.

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

• Known or suspected gastrointestinal obstruction, including paralytic ileus.

• Hypersensitivity to codeine (e.g., anaphylaxis) .

• Children younger than 12 years of age.

• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

• Hypersensitivity to codeine.

• 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.

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.

• Many acute pain conditions (e.g., 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.

• 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.

• 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.

• 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.

• Initiate treatment with 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.

• 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.

• 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. 2.1 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.

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.

• 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.

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.

Consider this risk when selecting an initial dose and when making dose adjustments. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene).

Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., 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.

The presence of risk factors for overdose should not prevent the management of pain in any patient.

Discuss the options for obtaining an opioid overdose reversal agent (e.g., 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. 2.3 Initial Dosage Initiating Treatment with Codeine Sulfate Tablets: Initiate treatment with Codeine Sulfate Tablets in a dosing range of to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia.

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. 2.4 Titration and Maintenance of Therapy Individually titrate Codeine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions.

Continually reevaluate patients receiving codeine sulfate to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse.

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.

Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 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.

For patients on Codeine Sulfate

Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., 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 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.

A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.

Tablets, USP 15 mg tablet: supplied as white to off-white biconvex tablets with “15” debossed on the scored side and “54 613” debossed on the other side.

NDC 0054-0243-24: 10 x 10 Unit-Dose 30 mg tablet: supplied as white to off-white biconvex tablets with “30” debossed on the scored side and “54 783” debossed on the other side.

NDC 0054-0244-24: 10 x 10 Unit-Dose NDC 0054-0244-25: Bottle of 100 Tablets 60 mg tablet: supplied as white to off-white biconvex tablets with “60” debossed on the scored side and “54 412” debossed on the other side.

NDC 0054-0245-25: Bottle of 100 Tablets Storage Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F).

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP/NF.

Blisters are not child-resistant.

Use child-resistant closure if dispensing to outpatient.

Tablets securely and dispose of properly.

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with Codeine Sulfate

Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between and 8 times the MRHD.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

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.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.

Opioid analgesics, including Codeine Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Animal Data: Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits.

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter.

Doses of and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight.

In an earlier study in hamsters, single oral doses of to 360 mg/kg level on Gestation Day 8 (oral; approximately to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg 2 basis) administered between Gestation Day and 12 reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m 2 basis) of codeine during organogenesis.

Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth.

This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.

The safety and effectiveness of Codeine Sulfate Tablets in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine.

In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children 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).

Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine.

• Codeine Sulfate Tablets are contraindicated for all children younger than 12 years of age.

• Codeine Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

• Avoid the use of Codeine Sulfate Tablets in adolescents 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.

Elderly patients (aged 65 years or older) may have increased sensitivity to codeine.

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of Codeine Sulfate

Tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression.

Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.