what symptom should you alert a patient taking a codeine-based antitussive to be aware of?

What is Codeine Sulfate and how is information technology used?

Codeine Sulfate is a prescription medicine used to care for the symptoms of balmy to moderately severe hurting. Codeine Sulfate may be used alone or with other medications.

Codeine Sulfate belongs to a class of drugs called Antitussives; Antitussives, Narcotic; Opioid Analgesics.

Information technology is non known if Codeine Sulfate is safe and effective in children younger than 12 years of age.

What are the possible side furnishings of Codeine Sulfate?

Codeine Sulfate may cause serious side furnishings including:

• noisy animate,
• sighing,
• shallow breathing,
• breathing that stops during sleep,
• slow heart rate,
• weak pulse,
• lightheadedness,
• confusion,
• unusual thoughts or behavior,
• feeling extreme happiness or sadness,
• convulsions (seizure),
• problems with urination,
• nausea,
• vomiting,
• loss of ambition,
• dizziness,
• worsening tiredness or weakness,
• agitation,
• hallucinations,
• fever,
• sweating,
• fast heart rate,
• muscle stiffness,
• twitching,
• loss of coordination, and
• diarrhea

Get medical help right away, if you take any of the symptoms listed above.

The virtually common side effects of Codeine Sulfate include:

• feeling featherbrained,
• drowsiness,
• constipation,
• nausea,
• vomiting, and
• stomach pain

Tell the doctor if you have any side effect that bothers you or that does not go abroad. These are not all the possible side effects of Codeine Sulfate. For more information, enquire your doctor or chemist. Call your doctor for medical advice near side effects. Yous may written report side effects to FDA at ane-800-FDA-1088.

Warning

DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE

Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.

DESCRIPTION

Chemically, codeine is Morphinan-6-ol,7,viii-didehydro-4,five-epoxy-3-methoxy-17-methyl-(5α,6α)-, sulfate (2:1) (salt), trihydrate. Its empirical formula is C₁₈H₂₁NO₃ and its molecular weight is 299.36.  Its structure is as follows:

Each tablet contains 15, 30, or 60 mg of codeine sulfate and the post-obit inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, and stearic acid.

3 pharmacies most 11430 have coupons for codeine sulfate (Brand Names:Codeine Sulfate for 15MG)

INDICATIONS

Codeine sulfate is an opioid analgesic indicated for the relief of mild to moderately severe hurting where the use of an opioid analgesic is appropriate.

DOSAGE AND ADMINISTRATION

Pick of patients for treatment with codeine sulfate should be governed by the same principles that use to the apply of similar opioid analgesics. Physicians should individualize treatment in every instance, using not-opioid analgesics, opioids on an as needed footing and/or combination products, and chronic opioid therapy in a progressive plan of hurting direction.

Individualization Of Dosage

Equally with whatsoever opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the option of the initial dose of codeine sulfate, attention should be given to the post-obit:

• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously;
• the reliability of the relative authority approximate used to summate the equivalent codeine sulfate dose needed;
• the patient'due south degree of opioid tolerance;
• the general status and medical condition of the patient;
• concurrent medications;
• the blazon and severity of the patient'southward pain;
• chance factors for corruption, addiction or diversion, including a prior history of corruption, addiction or diversion.

The post-obit dosing recommendations, therefore, tin simply exist considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual re-evaluation of the patient receiving codeine sulfate is of import, with special attending to the maintenance of pain command and the relative incidence of side effects associated with therapy. During chronic therapy, especially for noncancer-related pain, the continued need for the use of opioid analgesics should be re-assessed as appropriate.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

Initiation Of Therapy

The usual adult dosage for tablets is 15 mg to 60 mg repeated upward to every iv hours as needed for pain. The maximum 24 hour dose is 360 mg.

The initial dose should be titrated based upon the individual patient'south response to their initial dose of codeine. This dose can then be adjusted to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the codeine by the patient.

It should be kept in listen, however, that tolerance to codeine sulfate can develop with continued use and that the incidence of untoward effects is dose-related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain and are associated with an appreciably increased incidence of undesirable side furnishings.

Cessation Of Therapy

When the patient no longer requires therapy with codeine sulfate, doses should exist tapered gradually to foreclose signs and symptoms of withdrawal in the physically dependent patient.

HOW SUPPLIED

Dosage Forms And Strengths

Each fifteen mg tablet for oral administration contains 15 mg of codeine sulfate, USP. It is a white, biconvex tablet scored on one side, with forcefulness-indicating number "xv" debossed on the scored side and product identification number "54 613" debossed on the other side.

Each 30 mg tablet for oral administration contains 30 mg of codeine sulfate, USP. Information technology is a white, biconvex tablet scored on i side, with strength-indicating number "xxx" debossed on the scored side and product identification number "54 783" debossed on the other side.

Each 60 mg tablet for oral administration contains 60 mg of codeine sulfate, USP. Information technology is a white, arched tablet scored on one side, with strength-indicating number "lx" debossed on the scored side and product identification number "54 412" debossed on the other side.

Storage And Treatment

Codeine Sulfate

15 mg Tablet: white, biconvex tablets scored on one side, with strength-indicating number "15" debossed on the scored side and product identification number "54 613" debossed on the other side.

Unit dose, 25 tablets per blister bill of fare

NDC 0054-8155-24: 4 Cards per Carton

30 mg Tablet: white, arched tablets scored on one side, with strength-indicating number "xxx" debossed on the scored side and product identification number "54 783" debossed on the other side.

Unit dose, 25 tablets per blister card

NDC 0054-4156-24: four Cards per Carton
NDC 0054-0244-25: Bottles of 100 Tablets

60 mg Tablet: white, biconvex tablets scored on one side, with force-indicating number "60" debossed on the scored side and product identification number "54 412" debossed on the other side.

NDC 0054-4157-25: Bottles of 100 Tablets

Storage

Shop at Controlled Room Temperature, 15° to xxx°C (59° to 86°F).

Protect from moisture and light.

Dispense in well-airtight container as defined in the USP/NF.

Blisters are not child-resistant. Employ child-resistant closure if dispensing to outpatient.

All opioids are liable to diversion and misuse both by the general public and healthcare workers and should be handled accordingly.

Manufacturer details: n/a. Revised: May 2013

QUESTION

Medically speaking, the term "myalgia" refers to what blazon of pain? See Respond

SIDE EFFECTS

Serious agin reactions associated with codeine are respiratory depression and, to a bottom degree, circulatory depression, respiratory arrest, stupor, and cardiac arrest.

The nigh often observed agin reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.

Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis.

Other less oftentimes observed adverse reactions expected from opioid analgesics, including codeine sulfate, include:

Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope

Digestive System: abdominal cramps, anorexia, diarrhea, dry rima oris, gastrointestinal distress, pancreatitis

Nervous arrangement: feet, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness

Skin and Appendages: rash, sweating, urticaria

DRUG INTERACTIONS

CNS Depressants

Concurrent employ of other opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol) concomitantly with codeine sulfate tablets may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma. Use codeine sulfate with caution and in reduced dosages in patients taking these agents.

Mixed Agonist/Antagonist Opioid Analgesics

Mixed agonist/antagonist analgesics (i.eastward., pentazocine, nalbuphine, and butorphanol) should NOT exist administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as codeine sulfate. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic consequence and/or may precipitate withdrawal symptoms.

Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics including codeine sulfate, may issue in increased risk of urinary retention and/or astringent constipation, which may pb to paralytic ileus.

Antidepressants

Apply of MAO inhibitors or tricyclic antidepressants with codeine sulfate may increase the effect of either the antidepressant or codeine. MAOIs markedly potentiate the activity of morphine sulfate, the major metabolite of codeine. Codeine should non be used in patients taking MAOIs or inside fourteen days of stopping such treatment.

Metabolic Enzymes

Patients taking cytochrome P-450 enzyme inducers or inhibitors may demonstrate an altered response to codeine, therefore analgesic activeness should be monitored. Codeine sulfate is metabolized by the cytochrome P-450 3A4 and 2D6 isoenzymes [meet CLINICAL PHARMACOLOGY]. The concurrent use of drugs that preferentially induce codeine Ndemethylation (cytochrome P-450 3A4) may increment the plasma concentrations of codeine's inactive metabolite norcodeine. Drugs that are stiff inhibitors of codeine O-demethylation (cytochrome P-450 2D6) may subtract the plasma concentrations of codeine'southward active metabolites, morphine and morphine-half dozen-glucuronide. The contribution of these active metabolites to the overall analgesic event of codeine is not fully understood, but should be considered.

Drug-Laboratory Test Interaction

Codeine sulfate tablets may crusade an elevation of plasma amylase and lipase due to the potential of codeine to produce spasm of the sphincter of Oddi. Determination of these enzyme levels may be unreliable for some time subsequently an opiate agonist has been given.

Drug Corruption And Dependence

Controlled Substance

Codeine sulfate is an opioid agonist and is a Schedule II controlled substance. Codeine sulfate can be abused and is subject to criminal diversion.

Abuse

Drug addiction is characterized by compulsive use, use for not-medical purposes, and connected use despite harm or risk of harm. Drug habit is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

"Drug seeking" behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits about the finish of function hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(southward). "Physician shopping" to obtain additional prescriptions is mutual amidst drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may non be accompanied by concurrent tolerance and symptoms of physical dependence. The converse is as well true. In addition, abuse of opioids tin can occur in the absence of truthful addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing data, including quantity, frequency, and renewal requests is strongly brash.

Codeine is intended for oral use only. Abuse of codeine poses a adventure of overdose and death. The run a risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is ordinarily associated with transmission of infectious diseases such as hepatitis and HIV.

Proper cess of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are advisable measures that help to limit abuse of opioid drugs.

Infants built-in to mothers physically dependent on opioids will as well be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [encounter Utilize in Specific Populations, OVERDOSAGE].

Dependence

Tolerance is the demand for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of affliction progression or other external factors). Concrete dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, feet, backache, articulation pain, weakness, abdominal cramps, indisposition, nausea, anorexia, airsickness, diarrhea, or increased blood pressure, respiratory charge per unit, or heart rate.

In general, opioids should non be abruptly discontinued [see DOSAGE AND ADMINISTRATION).

WARNINGS

Included as part of the PRECAUTIONS department.

PRECAUTIONS

Death Related To Ultra-Rapid Metabolism Of Codeine To Morphine

Respiratory depression and decease accept occurred in children who received codeine in the mail service-operative menstruum post-obit tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the cistron for cytochrome P450 isoenzyme 2D6 [CYP2D6] or loftier morphine concentrations). Deaths accept also occurred in nursing infants who were exposed to high levels of morphine in chest milk because their mothers were ultra-rapid metabolizers of codeine [see Use in Specific Populations].

Some individuals may be ultra-rapid metabolizers considering of a specific CYP2D6 genotype (factor duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to i% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not bachelor for other ethnic groups. These individuals catechumen codeine into its active metabolite, morphine, more than apace 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 accept life-threatening or fatal respiratory low or feel signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [run across OVERDOSAGE].

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy hurting may be peculiarly sensitive to the respiratory depressant effects of codeine that has been chop-chop metabolized to morphine. Codeine is contraindicated for mail service-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS].

When prescribing codeine, healthcare providers should choose the lowest effective dose for the shortest flow of fourth dimension and inform patients and caregivers virtually these risks and the signs of morphine overdose [encounter Employ in Specific Populations, OVERDOSAGE].

Respiratory Depression

Respiratory low is the principal risk of codeine sulfate. Respiratory depression occurs more ofttimes in elderly or debilitated patients and in those suffering from weather condition accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly subtract pulmonary ventilation. Codeine produces dose-related respiratory depression.

Caution should be exercised when codeine sulfate is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilatory part is depressed. Opioid related respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied past hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Opioids, including codeine sulfate, should exist used with farthermost caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (east.g., astringent kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory low. In such patients, even usual therapeutic doses of codeine sulfate may increase airway resistance and subtract respiratory drive to the point of apnea. Culling non-opioid analgesics should exist considered, and codeine sulfate should exist employed only under conscientious medical supervision at the everyman effective dose in such patients [see OVERDOSAGE].

Misuse And Abuse of Opioids

Codeine sulfate is an opioid agonist of the morphine-type and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an deed subject to criminal penalty.

Codeine can be abused in a way similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing codeine sulfate in situations where the medico or pharmacist is concerned about an increased gamble of misuse, abuse, or diversion.

Misuse and corruption of codeine sulfate poses a significant run a risk to the abuser that could issue in overdose and decease. Codeine may exist abused by burdensome, chewing, snorting or injecting the production [see Drug Corruption and Dependence].

Concerns about abuse and habit should not prevent the proper direction of pain. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to foreclose and detect abuse or diversion of this product.

Interaction With Booze And Drugs Of Abuse

Codeine sulfate may be expected to take additive furnishings when used in conjunction with booze, other opioids, or illicit drugs that crusade central nervous arrangement depression, considering respiratory depression, hypotension, profound sedation, blackout or death may result.

Head Injury And Increased Intracranial Force per unit area

Respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure resulting from vasodilation post-obit CO2 retention may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids including codeine sulfate, produce adverse reactions which may obscure the clinical course of patients with head injuries.

Hypotensive Effect

Codeine sulfate may cause severe hypotension in an individual whose ability to maintain blood pressure level has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. Codeine sulfate may produce orthostatic hypotension and syncope in ambulatory patients.

Codeine sulfate should be administered with circumspection to patients in circulatory shock, every bit vasodilation produced by the drug may further reduce cardiac output and blood force per unit area.

Gastrointestinal Effects

Codeine sulfate should non be administered to patients with gastrointestinal obstruction, especially paralytic ileus considering codeine sulfate diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.

Chronic use of opioids, including codeine sulfate, may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder. Codeine sulfate may cause or aggravate constipation.

Administration of codeine sulfate may obscure the diagnosis or clinical course of patients with acute abdominal weather condition.

Use In Pancreatic/Biliary Tract Illness

Codeine sulfate should be used in circumspection in patients with biliary tract disease, including astute pancreatitis, as codeine sulfate may crusade spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.

Special Hazard Patients

As with other opioids, codeine sulfate should exist used with circumspection in elderly or debilitated patients and those with severe impairment of hepatic or renal role, hypothyrodism, Addison's disease, prostatic hypertrophy or urethral stricture [see Use in Specific Populations]. The usual precautions should be observed and the possibility of respiratory depression should be kept in listen.

Circumspection should be exercised in the administration of codeine sulfate to patients with CNS depression, acute alcoholism, and delirium tremens.

All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Driving And Operating Machinery

Patients should exist cautioned that codeine sulfate could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a automobile or operating machinery.

Patients should also be cautioned well-nigh the potential combined furnishings of codeine sulfate with other CNS depressants, including opioids, phenothiazines, sedative/hypnotics, and booze [meet DRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Two yr carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no prove of carcinogenicity in male person and female rats, respectively, at dietary doses upwardly to 70 and lxxx mg/kg/twenty-four hour period of codeine (approximately two times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years. Similiarly there was no testify of carcinogenicity activity in male person and female mice at dietary doses upwards to 400 mg/kg/day of codeine (approximately 5 times the maximum recommended daily dose of 360 mg/twenty-four hour period for adults on a mg/m² basis) for two years.

Mutagenesis

Codeine was non mutatgenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

Damage Of fertility

No animal studies were conducted to evaluate the effect of codeine on male or female person fertility.

Reproduction And Developmental Toxicology

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

A written report in hamsters administered 150 mg/kg bid of codeine (PO; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) reported the development of cranial malformations (i.e., meningoencephalocele) in several fetuses examined; besides equally the observation of increases in the pct of resorptions per litter examined. Doses of fifty and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal trunk weight. In an earlier written report in hamsters, doses of 73-360 mg/kg level (PO; approximately 2-8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/grand² footing), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (PO; approximately iii times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), in the toxic range for the adult fauna, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (SC; approximately 1.four times the recommended daily dose of 360 mg/solar day for adults on a mg/mg^two basis) 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/twenty-four hours for adults on a mg/m² ground) of codeine during organogenesis.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no acceptable and well-controlled studies in pregnant women. Codeine should be used during pregnancy just if the potential benefit justifies the potential take chances to the fetus.

Codeine has been shown to take embryolethal and fetotoxic effects (reduced fetal trunk weights and delayed or incomplete ossification) in the hamster, rat and mouse models at approximately two-4 times the maximum recommended human being dose of 360 mg/mean solar day based on a torso surface area comparison. Maternally toxic doses that were approximately vii times the maximum recommended human dose of 360 mg/day, were associated with prove of resorptions and incomplete ossification, including meningioencephalocele and cranioschisis. In contrast, codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses upwardly to 2 times the maximum recommended homo dose of 360 mg/day based on a body surface area comparing [run into Nonclinical Toxicology].

Nonteratogenic Effects

Neonatal codeine withdrawal has occurred in infants born to addicted and non-addicted mothers who had been taking codeine-containing medications in the days prior to delivery. Typical symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs occur shortly afterwards birth and may require specific handling.

Codeine (30 mg/kg) administered subcutaneously to meaning rats during pregnancy and for 25 days later delivery increased neonatal mortality at nascence. This dose is 0.8 times the maximum recommended man dose of 360 mg/day on a body area comparison.

Labor And Delivery

Opioid analgesics cross the placental barrier and may produce respiratory low and psycho-physiologic furnishings in neonates. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, elapsing, and frequency of uterine contractions. However, this issue is not consistent and may be showtime by an increased rate of cervical dilatation, which tends to shorten labor. The closer to delivery and the larger the dose used, the greater the possibility of respiratory low in the newborn. Opioid analgesics should be avoided during labor if commitment of a premature baby is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should exist observed closely for signs of respiratory depression. Resuscitation may be required [come across OVERDOSAGE]. A specific opioid adversary, such as naloxone or nalmefene, should be bachelor for reversal of opioid-induced respiratory depression in the neonate.

Nursing Mothers

Codeine is secreted into human being milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Nevertheless, some women are ultra-rapid metabolizers of codeine. These women achieve college-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously loftier serum morphine levels in their breastfed infants. Therefore, maternal apply of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The run a risk of infant exposure to codeine and morphine through chest milk should exist weighed against the benefits of breastfeeding for both the mother and the baby. Circumspection should exist exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of fourth dimension to attain the desired clinical effect. Mothers using codeine should exist informed nigh when to seek immediate medical intendance and how to identify the signs and symptoms of neonatal toxicity, such equally drowsiness or sedation, difficulty breastfeeding, animate difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as farthermost sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding [see WARNINGS AND PRECAUTIONS].

Pediatric Use

The safety and effectiveness and the pharmacokinetics of codeine sulfate in pediatric patients below the age of 18 have non been established. FDA has not required pediatric studies in ages birth to one month because there is show strongly suggesting that codeine would exist ineffective in this pediatric group since the metabolic pathways to metabolize codeine are not mature.

Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had testify of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been speedily metabolized to morphine. Codeine is contraindicated for postal service-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [meet CONTRAINDICATIONS].

Geriatric Use

Codeine may crusade confusion and over-sedation in the elderly. 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, and of concomitant disease or other drug therapy.

Renal Impairment

Codeine pharmacokinetics may be contradistinct in patients with renal failure. Clearance may exist decreased and the metabolites may accrue to much higher plasma levels in patients with renal failure every bit compared to patients with normal renal function. Starting time these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.

Hepatic Impairment

No formal studies take been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Commencement these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while advisedly monitoring for side furnishings.

OVERDOSE

Symptoms

Acute overdose of codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to shock or coma, miosis (mydriasis may occur in concluding narcosis or astringent hypoxia), skeletal muscle flaccidity, cold and clammy peel, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory plummet, cardiac abort, and death may occur.

Codeine sulfate may crusade miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose only are non pathognomonic (e.1000., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment

Primary attention should be given to the re-institution of adequate respiratory exchange through provision of a patent airway and establishment of assisted or controlled ventilation as necessary. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory stupor and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Induction of emesis is not recommended because of the potential for CNS depression and seizures. Activated charcoal is recommended if the patient is awake and able to protect his/her airway. In persons who are at risk for sharp onset of seizures or mental status depression, activated charcoal should be administered past medical or paramedical personnel capable of airway management to prevent aspiration in the consequence of spontaneous emesis. Severe agitation or seizures should exist treated with an intravenous benzodiazepine.

The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression resulting from overdosage or unusual sensitivity to opiate agonists, including codeine. Therefore, an appropriate dose of naloxone hydrochloride (see prescribing information for naloxone hydrochloride) should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Since the duration of activity of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered equally needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression secondary to codeine sulfate overdose.

In an private physically dependent on opioids, administration of the usual dose of the antagonist volition precipitate an astute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the caste of physical dependence and the dose of the antagonist administered. Use of an opioid adversary should be reserved for cases where such treatment is conspicuously needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, assistants of the antagonist should be initiated with care and titrated with smaller than usual doses.

CONTRAINDICATIONS

Codeine sulfate is contraindicated for postoperative hurting management in children who have undergone tonsillectomy and/or adenoidectomy [see WARNINGS AND PRECAUTIONS].

Codeine sulfate is contraindicated in patients with known hypersensitivity to codeine or whatsoever components of the product. Persons known to exist hypersensitive to certain other opioids may showroom cross-sensitivity to codeine.

Codeine sulfate is contraindicated in patients with respiratory depression in the absence of resuscitative equipment [see WARNINGS AND PRECAUTIONS].

Codeine sulfate is contraindicated in patients with acute or astringent bronchial asthma or hypercarbia.

Codeine sulfate is contraindicated in whatever patient who has or is suspected of having paralytic ileus.

CLINICAL PHARMACOLOGY

Machinery Of Activeness

Codeine sulfate is an opioid analgesic, related to morphine, but with less stiff analgesic properties. Codeine is selective for the mu receptor, but with a much weaker analogousness than morphine. The analgesic backdrop of codeine take been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

Effects Of The Central Nervous System (CNS)

The principal therapeutic activity of codeine sulfate is analgesia. Although the precise mechanism of the analgesic action is unknown, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal string and are likely to play a role in the expression and perception of analgesic effects. Some other CNS effects of codeine include anxiolysis, euphoria, and feelings of relaxation. Codeine sulfate causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Codeine sulfate and other related opioids depress the cough reflex by direct effect on the cough centre in the medulla. Codeine sulfate may also cause miosis.

Effects On The Gastrointestinal Tract And On Other Smooth Muscle

Gastric, biliary and pancreatic secretions may exist decreased by codeine. Codeine besides causes a reduction in motility and is associated with an increment in tone in the antrum of the stomach and duodenum. Digestion of nutrient in the small-scale intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The cease consequence may be constipation. Codeine can crusade a marked increase in biliary tract pressure as a result of the spasm of the sphincter of Oddi. Codeine may as well crusade spasms of the sphincter of the urinary bladder.

Furnishings On The Cardiovascular System

Codeine produces peripheral vasodilation which may effect in orthostatic hypotension and fainting. Release of histamine tin occur, which may play a function in opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, ruby-red eyes, and sweating.

Endocrine System

Opioid agonists such as codeine sulfate have been shown to accept a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They as well stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagons in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Allowed System

Codeine has been shown to have a diverseness of furnishings on components of the immune organisation in in vitro and creature models. The clinical significance of these findings is unknown.

Pharmacodynamics

Codeine concentrations do not correlate with brain concentration or relief of hurting.

The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid apply, age and general medical status. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

Pharmacokinetics

Absorption

Codeine is absorbed from the alimentary canal with maximum plasma concentration occurring 60 minutes mail service assistants.

Food Effects

When 60 mg codeine sulfate was administered thirty minutes after ingesting a high fat/high calorie meal, in that location was no significant change in the rate and extent of absorption of codeine.

Steady-land

Administration of 15 mg codeine sulfate every iv hours for 5 days resulted in steady-country concentrations of codeine, morphine, morphine-iii-glucuronide (M3G) and morphine-6-glucuronide (M6G) inside 48 hours.

Distribution

Codeine has been reported to take an credible volume of distribution of approximately 3-6 L/kg, indicating all-encompassing distribution of the drug into tissues. Codeine has depression plasma protein binding with about vii-25% of codeine bound to plasma proteins.

Metabolism

About 70-eighty% of the administered dose of codeine is metabolized past conjugation with glucuronic acid to codeine-6glucuronide (C6G) and via O-demethylation to morphine (about five-ten%) and North-demethylation to norcodeine (about x%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-three-glucuronide (M3G) and morphine-half-dozen-glucuronide (M6G). Morphine and M6G are known to have analgesic action in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

Emptying

Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine. Plasma half-lives of codeine and its metabolites accept been reported to be approximately iii hours.

PATIENT INFORMATION

• Propose patients that codeine sulfate is a narcotic hurting reliever and may be habit forming. It should be taken only as directed.
• Advise patients that some people have a genetic variation that results in codeine irresolute into morphine more rapidly and completely than other people. Virtually people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow animate. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may exist at greatest chance based on reports of several deaths in this population due to respiratory depression. Codeine is contraindicated in children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression.
• Advise patients that nursing mothers taking codeine can have college morphine levels in their breast milk if they are ultra-rapid metabolizers. These college levels of morphine in breast milk may atomic number 82 to life-threatening or fatal side effects in nursing babies. Suggest nursing mothers to watch for signs of morphine toxicity in their infants which includes increased sleepiness (more than usual), difficulty breastfeeding, animate difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they detect these signs and, if they cannot reach the medico right away, to take the babe to an emergency room or call 911 (or local emergency services).
• Advise patients that the dose of codeine sulfate should not be adjusted without consulting with your doctor.
• Advise patients that codeine may cause drowsiness, dizziness, or lightheadedness and may impair the mental and/or physical abilities required for the performance of potentially chancy tasks such every bit driving a car or operating mechanism.
• Advise patients started on codeine sulfate or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely afflicted. Propose patients not to combine codeine sulfate with alcohol or other central nervous organization depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous condiment effects may occur, resulting in serious injury or expiry.
• Propose patients that codeine sulfate is a potential drug of abuse, and should exist protected from theft. It should never be given to anyone other than the private for whom information technology was prescribed.
• Suggest patients to go along codeine sulfate in a secure identify out of the reach of children.
• Advise patients of the potential for severe constipation when taking codeine sulfate; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of therapy.
• Suggest patients of the most common adverse events that may occur while taking codeine sulfate: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, constipation, and sweating.
• If patients have been receiving treatment with codeine sulfate for more than a few weeks and cessation of therapy is indicated, they should be counseled on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. The physician should provide a dose schedule to accomplish a gradual discontinuation of the medication.
• Women of childbearing potential who become or are planning to get significant should consult a physician prior to initiating or continuing therapy with codeine sulfate.
• Safe use in pregnancy has not been established. Prolonged use of opioid analgesics during pregnancy may cause fetal/neonatal physical dependence, and neonatal withdrawal may occur.

From

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Source: https://www.rxlist.com/codeine-sulfate-drug.htm

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