Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL Solution, 473 mL — NDC 0713-0823-75 (Billing 00713-0823-75)
This is a package of 473 mL of Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL Solution from Cosette Pharmaceuticals, Inc., marketed since Dec 2025 and currently FDA-listed; retail pharmacies pay about $0.0697 per mL (NADAC). It is this product's only package size.
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 048489
- GCN: 13971
- GPI-14 (Medi-Span): 43995202341210
- HICL (First Databank): 000345
- AHFS class code: 28:08.08.00
- RxCUI (RxNorm): 991486
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Opioid Agonist class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Codeine is used to relieve pain. It is also used to relieve cough. Codeine belongs to a class of medications called opiate (narcotic) analgesics and to a class of medications called antitussives. When codeine is used to treat pain, it works by changing the way the brain and nervous system respond to pain. When codeine is used to reduce coughing, it works by decreasing the activity in the part of the brain that causes coughing. Codeine is also available in combination with acetaminophen and aspirin, and as an ingredient in many cough and cold medications. This monograph only includes informatio...
Read the full MedlinePlus article ↗Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.070 | $32.97 / 473 ml |
| Medicaid paysCMS SDUD · 12 mo | $0.1696 | $80.22 / 473 ml |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 00713-0823-75 You're viewing this Main listing | 473 mL in 1 BOTTLE, PLASTIC | 2025-12-19 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mLthis 00713-0823-75 | Cosette | 473 ml | $0.070 | AA | Availability likely | — |
| Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL 27808-0065-02 | Cranbury | 473 ml | $0.070 | AA | Availability likely | — |
| Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL 17856-0065-01 | ATLANTIC | 72 cups | — | AA | FDA listed | — |
| Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL 70752-0139-06 | QUAGEN | 118 ml | — | AA | FDA listed | — |
| Promethazine Hydrochloride and Codeine Phosphate 6.25 mg/5mL; 10 mg/5mL 72162-2042-02 | Bryant | 473 ml | — | AA | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 3K9958V90M
A liquid solvent derived from fermentation or chemical synthesis. In medicines, alcohol dissolves active ingredients, helps preserve the product, and improves how the body absorbs certain drugs.
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UNII XF417D3PSL
Anhydrous citric acid is a sour, crystalline powder derived from citric acid with water removed. In medicines, it acts as a buffer to control pH, adds tartness to improve taste, and helps tablets disintegrate.
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UNII PQ6CK8PD0R
Ascorbic acid, also known as vitamin C, is a white crystalline powder. It serves as an antioxidant to prevent degradation of other ingredients and may also function as a preservative in the formulation.
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UNII 9DBA0SBB0L
A synthetic red dye derived from coal tar used as a colorant in medicines and cosmetics. It gives tablets, capsules, and liquids their red or pink appearance for identification and visual appeal.
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UNII 7FLD91C86K
Edetate disodium is a chemical compound that binds and removes certain metal ions. In medicines, it acts as a preservative and stabilizer by preventing metals like calcium from interfering with the product's shelf life and consistency.
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UNII H3R47K3TBD
FD&C Blue No. 1 is a synthetic blue dye approved for use in foods and medicines. It serves as a colorant to give the medication its distinctive appearance and help with product identification.
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UNII A2I8C7HI9T
Methylparaben is a preservative derived from benzoic acid that prevents growth of bacteria, fungi, and mold in medicines. It extends the product's shelf life and maintains safety during storage.
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UNII FV98Z8GITP
A natural flavoring from mint plants. It's added to medicines to mask bitter tastes and improve how the medicine tastes, making it easier to take.
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UNII 3OKE88I3QG
A natural flavoring derived from peach fruit. It enhances taste in oral medicines to make them more palatable, especially for patients who might otherwise resist taking the medication.
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UNII 6DC9Q167V3
Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
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UNII Z8IX2SC1OH
Propylparaben is a chemical preservative used to prevent bacterial and fungal growth in medicines and personal care products. It helps extend shelf life and maintain product safety during storage.
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UNII SB8ZUX40TY
Saccharin sodium is an artificial sweetener made from saccharin salt. It's added to medicines to improve taste, especially in liquid formulations for children or bitter drugs.
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UNII OJ245FE5EU
Sodium benzoate is a salt derived from benzoic acid, a preservative. It's added to medicines to prevent growth of bacteria, fungi, and other microorganisms that could spoil the product.
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UNII 1Q73Q2JULR
Sodium citrate is a salt derived from citric acid. It works as a buffer to maintain the medicine's pH level and may also help improve taste or act as a preservative in the formulation.
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UNII 4VON5FNS3C
Sodium metabisulfite is a preservative derived from sulfur compounds. It prevents microbial growth and oxidation in medicines, helping extend shelf life and maintain product stability.
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UNII C151H8M554
A natural sugar derived from sugar cane or sugar beets. It's used as a sweetener, filler, and binder to improve taste, add bulk, and help hold tablet or capsule ingredients together.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
17 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; PROMETHAZINE AND RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse Promethazine HCl and Codeine Phosphate Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Reserve Promethazine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing Promethazine HCl and Codeine Phosphate Oral Solution, prescribe Promethazine HCl and Codeine Phosphate Oral Solution for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. [ see Warnings and Precautions (5.1) ].
Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Promethazine HCl and Codeine Phosphate Oral Solution. Monitor for respiratory depression, especially during initiation of Promethazine HCl and Codeine Phosphate Oral Solution therapy or when used in patients at higher risk [ see Warnings and Precautions (5.2) ]. Accidental Ingestion Accidental ingestion of even one dose of Promethazine HCl and Codeine Phosphate Oral Solution, especially by children, can result in a fatal overdose of codeine [ see Warnings and Precautions (5.2) ].
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. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [ see Warnings and Precautions (5.3) ]. Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ].
Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution 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. Promethazine and Respiratory Depression in Children Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine [ see Warnings and Precautions (5.4) ].
Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering Promethazine HCl and Codeine Phosphate Oral Solution. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering Promethazine HCl and Codeine Phosphate Oral Solution [ see Dosage and Administration (2.1) , Warnings and Precautions (5.7) ].
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, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of Promethazi… [Excerpted — this section continues on DailyMed.]
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Promethazine HCl and Codeine Phosphate Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. Important Limitations of Use Not indicated for pediatric patients under 18 years of age [ see Use in Specific Populations (8.4) ]. Contraindicated in pediatric patients under 12 years of age [ see Contraindications (4) , Use in Specific Populations (8.4) ].
Contraindicated in pediatric patients 12 to 18 years of age after tonsillectomy or adenoidectomy [ see Contraindications (4) , Use in Specific Populations (8.4) ]. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [ see Warnings and Precautions (5.1) ], reserve Promethazine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.
Promethazine HCl and Codeine Phosphate Oral Solution is a combination of codeine, an opioid agonist; and promethazine, a phenothiazine, indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. ( 1 ) Important Limitations of Use ( 1 ) Not indicated for pediatric patients under 18 years of age. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Promethazine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Adults 18 years of age and older : 5 mL every 4 to 6 hours as needed, not to exceed 6 doses (30 mL) in 24 hours. ( 2.2 ) Measure Promethazine HCl and Codeine Phosphate Oral Solution with an accurate milliliter measuring device. ( 2.1 , 5.7 ) Do not increase the dose or dosing frequency.
( 2.1 ) Prescribe for the shortest duration consistent with treatment goals. ( 2.3 ) Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. ( 2.3 ) Reevaluate patient prior to refilling.
(2.3)
2.1Important Dosage and Administration Instructions Administer Promethazine HCl and Codeine Phosphate Oral Solution by the oral route only. Always use an accurate milliliter measuring device when administering Promethazine HCl and Codeine Phosphate Oral Solution to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [ see Warnings and Precautions (5.7) ] .
For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use.
Advise patients not to increase the dose or dosing frequency of Promethazine HCl and Codeine Phosphate Oral Solution because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.1) , Overdosage (10) ]. The dosage of Promethazine HCl and Codeine Phosphate Oral Solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [ see Dosage and Administration (2.3) , Warnings and Precautions (5.6) ].
2.2Recommended Dosage Adults 18 years of age and older: 5 mL every 4 to 6 hours as needed, not to exceed 6 doses (30 mL) in 24 hours.
2.3Monitoring, Maintenance, and Discontinuation of Therapy Prescribe Promethazine HCl and Codeine Phosphate Oral Solution for the shortest duration that is consistent with individual patient treatment goals [ see Warnings and Precautions (5.1) ]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy [ see Warnings and Precautions (5.2) ]. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Warnings and Precautions (5.6) ].
If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with Promethazine HCl and Codeine Phosphate Oral Solution, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [ see Warnings and Precautions (5.1) ]. Do not abruptly discontinue Promethazine HCl and Codeine Phosphate Oral Solution in a physically-dependent patient [ see Drug Abuse and Dependence (9.3) ]. When a patient who has been taking Promethazine HCl and Codeine Phosphate Oral Solution regularly and may be physically dependent no longer requires therapy with Promethazine HCl and Codeine Phosphate Oral Solution, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal.
If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.
2.1Important Dosage and Administration Instructions Administer Promethazine HCl and Codeine Phosphate Oral Solution by the oral route only. Always use an accurate milliliter measuring device when administering Promethazine HCl and Codeine Phosphate Oral Solution to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [ see Warnings and Precautions (5.7) ] .
For pr… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a flavored syrup base [ see Description (11) ]. Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a clear, purple red, peach-mint flavor syrup. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for: All children younger than 12 years of age [ see Warnings and Precautions (5.2 , 5.3 , 5.5 ), Use in Specific Populations (8.4) ]. Postoperative pain management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Warnings and Precautions (5.2 , 5.3 ) ]. Promethazine HCl and Codeine Phosphate Oral Solution is also contraindicated in patients with: Significant respiratory depression [ see Warnings and Precautions (5.2) ].
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [ see Warnings and Precautions (5.6) ] . Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions (5.11) ]. A history of an idiosyncratic reaction to promethazine or to other phenothiazines [ see Warnings and Precautions (5.14) ].
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [ see Warnings and Precautions (5.16) , Drug Interactions (7.6) ]. Hypersensitivity to codeine, promethazine, or any of the inactive ingredients in Promethazine HCl and Codeine Phosphate Oral Solution [ see Adverse Reactions (6) ]. Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine.
Children younger than 12 years of age. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.
( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Concurrent use of monoamine oxidase inhibitor (MAOI) therapy or within the last 14 days. ( 4 ) History of an idiosyncratic reaction to promethazine or to other phenothiazines.
( 4 ) Hypersensitivity to codeine or other opiates, promethazine, or any of the inactive ingredients in Promethazine HCl and Codeine Phosphate Oral Solution. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS See Boxed WARNINGS Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients : Monitor closely, particularly during initiation of therapy. ( 5.6 ) Activities requiring mental alertness : Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. ( 5.8 ) Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors : Avoid use.
May increase intracranial pressure and obscure the clinical course of head injuries. ( 5.12 ) Neuroleptic Malignant Syndrome : Monitor during therapy. ( 5.13 ) Paradoxical Reactions : Monitor during therapy.
( 5.14 ) Seizures in patients with seizure disorders : Monitor during therapy. ( 5.15 ) Bone marrow depression : Use with caution in patients with bone marrow depression. ( 5.17 ) Severe hypotension : Monitor during initiation of therapy.
Avoid use in patients with circulatory shock. ( 5.18 ) Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.20 )
5.1Addiction, Abuse, and Misuse Promethazine HCl and Codeine Phosphate Oral Solution contains codeine, a Schedule V controlled substance. As an opioid, Promethazine HCl and Codeine Phosphate Oral Solution exposes users to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence (9) ] , which can lead to overdose and death [ see Overdosage (10) ]. Reserve Promethazine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.
Assess each patient’s risk prior to prescribing Promethazine HCl and Codeine Phosphate Oral Solution, prescribe Promethazine HCl and Codeine Phosphate Oral Solution for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Promethazine HCl and Codeine Phosphate Oral Solution.
Addiction can occur at recommended dosages and if the drug is misused or abused. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Consider these risks when prescribing or dispensing Promethazine HCl and Codeine Phosphate Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [ see Patient Counseling Information (17) ]. 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.
5.2Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including codeine, one of the active ingredients in Promethazine HCl and Codeine Phosphate Oral Solution. Codeine produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to the active metabolite morphine [ see Warnings and Precautions (5.3) ].
Promethazine exerts a depressant effect on the respiratory center that is independent of and additive to that of other respiratory depressants, including codeine [ see Warning… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, abuse, and misuse [ see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.3) ] Life-threatening respiratory depression [ see Warnings and Precautions (5.2, 5.3 , 5.4 , 5.5 , 5.6 ), Overdosage (10) ] Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children [ see Warnings and Precautions (5.3) ] Accidental overdose and death due to medication errors [ see Warnings and Precautions (5.7) ] Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.8) ] Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.10) ] Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.11) ] Increased intracranial pressure [ see Warnings and Precautions (5.12) ] Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.12) ] Neuroleptic Malignant Syndrome [ see Warnings and Precautions (5.13) ] Paradoxical reactions, including dystonias [ see Warnings and Precautions (5.14) ] Seizures [ see Warnings and Precautions (5.15) ] Interactions with MAOI [ see Warnings and Precautions (5.16) ] Bone marrow suppression [ see Warnings and Precautions (5.17) ] Severe hypotension [ see Warnings and Precautions (5.18) ] Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.19) ] Adrenal insufficiency [ see Warnings and Precautions (5.20) ] The following adverse reactions have been identified during clinical studies, in the literature, or during postapproval use of codeine and/or promethazine.
Because these reactions may be 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. The most common adverse reactions to Promethazine HCl and Codeine Phosphate Oral Solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, sweating. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with codeine, one of the ingredients in Promethazine HCl and Codeine Phosphate Oral Solution.
Body as a whole : Coma, death, fatigue, falling injuries, lethargy. Cardiovascular : Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush. Central Nervous System : Ataxia, diplopia, facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tinnitus, tremor, vertigo.
Dermatologic : Flushing, hyperhidrosis, photosensitivity, pruritus, rash, urticaria. Endocrine/Metabolic : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology (12.2) ]. Gastrointestinal : Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, jaundice, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary : Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention.
Hematologic : Bone marrow suppression, agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. Laboratory : Increases in serum amylase. Musculoskeletal : Arthralgia, backache, muscle spasm.
Ophthalmic : Blurred vision, miosis (constricted pupils), visual disturbances. Paradoxical Reactions : Dystonias, torticollis, tongue prot… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS No specific drug interaction studies have been conducted with Promethazine HCl and Codeine Phosphate Oral Solution. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected.
( 7.5 ) Muscle relaxants : Avoid concomitant use. ( 7.7 ) Diuretics : Codeine may reduce the efficacy of diuretics. Monitor for reduced effect.
( 7.8 ) Anticholinergic drugs : Concurrent use may cause paralytic ileus. ( 5.11 , 7.9 )
7.1Inhibitors of CYP3A4 The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Promethazine HCl and Codeine Phosphate Oral Solution is achieved [ see Warnings and Precautions (5.9) ].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels [ see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution while taking a CYP3A4 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
7.2CYP3A4 Inducers The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, or phenytoin, can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [ see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [ see Warnings and Precautions (5.9) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [ see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.
7.3Inhibitors of CYP2D6 Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, or quinidine, can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced efficacy [ see Clinical Pharmacology (12.3) ]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [ see Clinical Pharmacology (12.3) ].
Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking inhibitors of CYP2D6.
7.4Benzodiazepines, and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, ant… [Excerpted — this section continues on DailyMed.]
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy : Avoid use in pregnant women. May cause fetal harm. ( 8.1 ) Lactation : Breastfeeding not recommended. ( 8.2 ) Renal Impairment : Use with caution in patients with severe renal impairment. ( 8.6 ) Hepatic Impairment : Use with caution in patients with severe hepatic impairment. ( 8.7 )
8.1Pregnancy Risk Summary Promethazine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions (5.19) , Clinical Considerations ]. There are no available data with Promethazine HCl and Codeine Phosphate Oral Solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes.
Published studies with codeine have reported inconsistent findings and have important methodological limitations ( see Data ). There are reports of respiratory depression when codeine is used during labor and delivery ( see Clinical Considerations ). Reproductive toxicity studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution; however, studies are available with individual active ingredients ( see Data ).
In animal reproduction studies, codeine administered by the oral route to pregnant rats during the period of organogenesis increased resorptions and decreased fetal weights at a dose approximately 25 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity ( see Data ). For pregnant mice and rats that received promethazine at doses 0.2 and 3-6 times the MRHD, during various periods of gestation, there were findings of increased fetal resorptions and skeletal fragility, decreased pup weight, and developmental delays of pups ( see Data ).
Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics 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 [ see Warnings and Precautions (5.19) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.
An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including Promethazine HCl and Codeine Phosphate Oral Solution, 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 opioids during labor for signs of excess sedation and respiratory depression. Data Human Data Published data from case-control and observational studies on codeine use during pregnancy are inconsistent in their findings. Some studies of codeine exposure showed an increased risk of overall congeni… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Promethazine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions (5.19) , Clinical Considerations ]. There are no available data with Promethazine HCl and Codeine Phosphate Oral Solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes.
Published studies with codeine have reported inconsistent findings and have important methodological limitations ( see Data ). There are reports of respiratory depression when codeine is used during labor and delivery ( see Clinical Considerations ). Reproductive toxicity studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution; however, studies are available with individual active ingredients ( see Data ).
In animal reproduction studies, codeine administered by the oral route to pregnant rats during the period of organogenesis increased resorptions and decreased fetal weights at a dose approximately 25 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity ( see Data ). For pregnant mice and rats that received promethazine at doses 0.2 and 3-6 times the MRHD, during various periods of gestation, there were findings of increased fetal resorptions and skeletal fragility, decreased pup weight, and developmental delays of pups ( see Data ).
Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics 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 [ see Warnings and Precautions (5.19) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.
An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including Promethazine HCl and Codeine Phosphate Oral Solution, 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 opioids during labor for signs of excess sedation and respiratory depression. Data Human Data Published data from case-control and observational studies on codeine use during pregnancy are inconsistent in their findings. Some studies of codeine exposure showed an increased risk of overall congenital malformations while others did not.
An increased risk of specific malformations with codeine exposure such as respiratory malformations, spina bifida and congenital heart defects were reported in some studies. The majority of studies examining the use of promethazine in pregnancy did not find an association with an increas… [Excerpted — this section continues on DailyMed.]
🧒 Pediatric Use ▾
8.4Pediatric Use Promethazine HCl and Codeine Phosphate Oral Solution is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of codeine in these patients [ see Indications (1) , Warnings and Precautions (5.5) ]. Life-threatening respiratory depression and death have occurred in children who received codeine [ see Warnings and Precautions (5.2) ]. 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. Life-threatening respiratory depression and death have also occurred in children who received promethazine [ see Warnings and Precautions (5.4) ]. Because of the risk of life-threatening respiratory depression and death: Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for all children younger than 12 years of age [ see Contraindications (4) ].
Promethazine HCl and Codeine Phosphate Oral Solution is 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 Promethazine HCl and Codeine Phosphate Oral Solution 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 [ see Warnings and Precautions (5.3 , 5.6) ] .
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution in geriatric populations. Use caution when considering the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients 65 years of age or older. Elderly patients may have increased sensitivity to codeine; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [ see Warnings and Precautions (5.6) ].
Respiratory depression is the chief risk for elderly patients treated with opioids, including Promethazine HCl and Codeine Phosphate Oral Solution. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [ see Warnings and Precautions (5.6 , 5.10) ]. 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, monitor these patients closely for respiratory depression, sedation, and hypotension.
🆘 Overdosage ▾
10 OVERDOSAGE Clinical Presentation Codeine Acute overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, partial or complete airway obstruction, atypical snoring, hypotension, hypoglycemia, circulatory collapse, cardiac arrest, and death. Codeine may cause miosis, even in total darkness.
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [ see Clinical Pharmacology (12.2) ]. Promethazine Signs and symptoms of overdosage with promethazine range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death.
Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur.
A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms (dry mouth, fixed dilated pupils, flushing, tachycardia, hallucinations, gastrointestinal symptoms, convulsions, urinary retention, cardiac arrhythmias and coma) may be observed. Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia.
Treatment of Overdose Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of Promethazine HCl and Codeine Phosphate Oral Solution together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.
Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug. The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose.
For clinically significant respiratory or circulatory depression secondary to codeine overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the duration of opioid reversal is expected to be less than the duration of action of codeine in Promethazine HCl and Codeine Phosphate Oral Solution, carefully monitor the patient until spontaneous respiration is reliably reestablished.
If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. The respiratory depressant effects of promethazine are not reversed by opioid antagonists, such as naloxone. Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose.
Hemodialysis is not routinely used to enhance the elimination of codeine or promethazine from the body.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Codeine Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic and antitussive properties of codeine have been speculated to come from its conversion to morphine. The precise mechanism of action of codeine and other opiates is not known; however, codeine is believed to act centrally on the cough center.
In excessive doses, codeine will depress respiration. Promethazine Promethazine is a phenothiazine derivative, which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. Promethazine possesses antihistamine (H 1 receptor antagonist), antiemetic, sedative, and anticholinergic effects.
It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.
12.2Pharmacodynamics Codeine Effects on the Central Nervous System Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Codeine causes miosis, even in total darkness.
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.
Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [ see Adverse Reactions (6) ].
They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [ see Adverse Reactions (6) ].
Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Adverse Reaction Relationships There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. Promethazine Promethazine competitively antagonize H 1 receptors located in most of the smooth muscle including the gastrointestinal tract, ut… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Codeine Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic and antitussive properties of codeine have been speculated to come from its conversion to morphine. The precise mechanism of action of codeine and other opiates is not known; however, codeine is believed to act centrally on the cough center.
In excessive doses, codeine will depress respiration. Promethazine Promethazine is a phenothiazine derivative, which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. Promethazine possesses antihistamine (H 1 receptor antagonist), antiemetic, sedative, and anticholinergic effects.
It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Promethazine HCl and Codeine Phosphate Oral Solution is supplied as a clear, purple red, peach-mint flavor syrup containing promethazine HCl 6.25 mg/5 mL, codeine phosphate 10 mg/5 mL and alcohol 8% (v/v). It is available as follows: Bottles of 16 fluid ounces (473 mL), NDC 0713-0823-75. Keep bottles tightly closed.
Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in tight, light-resistant container (USP/NF) with a child-resistant closure. Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters.
Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed. DEA Order Form Required.
📋 Description ▾
11 DESCRIPTION Promethazine HCl and Codeine Phosphate Oral Solution contains codeine, an opioid agonist, and promethazine, a phenothiazine. Each 5 mL of Promethazine HCl and Codeine Phosphate Oral Solution contains 10 mg of codeine phosphate and 6.25 mg of promethazine hydrochloride for oral administration. Promethazine HCl and Codeine Phosphate Oral Solution has a pH between 4.8 and 5.4 and contains alcohol 8% (v/v).
Promethazine HCl and Codeine Phosphate Oral Solution also contains the following inactive ingredients: anhydrous citric acid, ascorbic acid, D&C Red # 33, edetate disodium, FD&C Blue #1, methylparaben, peach-mint flavor, propylene glycol, propylparaben, purified water, saccharin sodium, sodium benzoate, sodium citrate anhydrous, sodium metabisulfite, sucrose. Codeine Phosphate The chemical name for codeine phosphate is 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic.
The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. The molecular weight is 406.37.
Its molecular formula is C 18 H 21 NO 3 •H 3 PO 4 • ½ H 2 O, and it has the following chemical structure. Promethazine Hydrochloride The chemical name for promethazine hydrochloride, a phenothiazine derivative, is (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air.
It is soluble in water and freely soluble in alcohol. The molecular weight is 320.88. Its molecular formula is C 17 H 20 N 2 S•HCl, and it has the following chemical structure. chemicalstructure-codeine chemicalstructure-promethazine
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse, and Misuse Inform patients that the use of Promethazine HCl and Codeine Phosphate Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [ see Warnings and Precautions (5.1) ]. Instruct patients not to share Promethazine HCl and Codeine Phosphate Oral Solution with others and to take steps to protect Promethazine HCl and Codeine Phosphate Oral Solution from theft or misuse.
Important Dosing and Administration Instructions Instruct patients how to measure and take the correct dose of Promethazine HCl and Codeine Phosphate Oral Solution. Advise patients to measure Promethazine HCl and Codeine Phosphate Oral Solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage.
Advise patients to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [ see Dosage and Administration (2.1) , Warnings and Precautions (5.7) ]. Advise patients not to increase the dose or dosing frequency of Promethazine HCl and Codeine Phosphate Oral Solution because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.2) , Overdosage (10) ]. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Promethazine HCl and Codeine Phosphate Oral Solution and that it can occur even at recommended dosages [ see Warnings and Precautions (5.2) ].
Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [ see Warnings and Precautions (5.2) ]. Instruct patients to take steps to store Promethazine HCl and Codeine Phosphate Oral Solution securely and to properly dispose of unused Promethazine HCl and Codeine Phosphate Oral Solution in accordance with the local state guidelines and/or regulations.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Advise caregivers that Promethazine HCl and Codeine Phosphate Oral Solution is not indicated for pediatric patients under 18 years of age, and is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Activities Requiring Mental Alertness Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as Promethazine HCl and Codeine Phosphate Oral Solution may produce marked drowsiness [ see Warnings and Precautions (5.8) ].
Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol Inform patients and caregivers that potentially fatal additive effects may occur if Promethazine HCl and Codeine Phosphate Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with benzodiazepines or other CNS depressants and to not use alcohol while taking Promethazine HCl and Codeine Phosphate Oral Solution [ see Warnings and Precautions (5.10) , Drug Interactions (7.4) ].
Constipation Advise patients of the potential for severe constipation [ see Warnings and Precautions (5.11), Adverse Reactions (6) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Promethazine HCl and Codeine Phosphate Oral Solution. Advise patients how to recognize such a… [Excerpted — this section continues on DailyMed.]
💬 Medication Guide ▾
MEDICATION GUIDE Promethazine (proe METH a zeen) Hydrochloride and Codeine (KOE deen) Phosphate Oral Solution, C-V What is the most important information I should know about Promethazine Hydrochloride and Codeine Phosphate Oral Solution? Promethazine Hydrochloride and Codeine Phosphate Oral Solution is not for children under 18 years of age. Promethazine Hydrochloride and Codeine Phosphate Oral Solution can cause serious side effects, including: Addiction, abuse and misuse.
Taking Promethazine Hydrochloride and Codeine Phosphate Oral Solution or other medicines that contain an opioid can cause addiction, abuse, and misuse, which can lead to overdose and death. This can happen even if you take Promethazine Hydrochloride and Codeine Phosphate Oral Solution exactly as prescribed by your healthcare provider. Your risk of addiction, abuse, and misuse is increased if you or a family member has a history of drug or alcohol abuse or addiction, or mental health problems.
Do not share your Promethazine Hydrochloride and Codeine Phosphate Oral Solution with other people. Keep Promethazine Hydrochloride and Codeine Phosphate Oral Solution in a safe place away from children. Life-threatening breathing problems (respiratory depression).
Promethazine Hydrochloride and Codeine Phosphate Oral Solution can cause breathing problems (respiratory depression) that can happen at any time during treatment and can lead to death. Your risk of breathing problems is greatest when you first start taking Promethazine Hydrochloride and Codeine Phosphate Oral Solution, are taking other medicines that can cause breathing problems, have certain lung problems, are elderly or have certain other health problems. Children are at higher risk for respiratory depression.
Breathing problems can happen even if you take Promethazine Hydrochloride and Codeine Phosphate Oral Solution exactly as prescribed by your healthcare provider. Call your healthcare provider or get emergency medical help right away if anyone taking Promethazine Hydrochloride and Codeine Phosphate Oral Solution, or your breastfeeding baby has any of the symptoms below: increased sleepiness confusion difficulty breathing shallow breathing limpness Keep Promethazine Hydrochloride and Codeine Phosphate Oral Solution in a safe place away from children.
Accidental use of even 1 dose of Promethazine Hydrochloride and Codeine Phosphate Oral Solution, especially by a child, is a medical emergency and can cause breathing problems (respiratory depression) which can lead to death. If a child accidentally takes Promethazine Hydrochloride and Codeine Phosphate Oral Solution, get emergency help right away. Overdose and death due to medicine dosing errors.
Overdose and death can happen if you measure the wrong dose of Promethazine Hydrochloride and Codeine Phosphate Oral Solution. Always use an accurate milliliter (mL) measuring device to measure the correct amount of Promethazine Hydrochloride and Codeine Phosphate Oral Solution. Do not use a household teaspoon to measure your medicine.
You may accidentally take too much. You can ask your pharmacist for the measuring device you should use and how to measure the correct dose. Breathing problems (respiratory depression) that can lead to death and opioid withdrawal can happen if you start taking or stop taking other medicines while taking Promethazine Hydrochloride and Codeine Phosphate Oral Solution, including: certain antibiotics certain medicines to treat a fungal infection certain medicines to treat Human Immunodeficiency Virus (HIV)-1 infection, Acquired Immune Deficiency Syndrome (AIDS), or Hepatitis C rifampin carbamazepine phenytoin Severe drowsiness, breathing problems (respiratory depression), coma, and death can happen in adults and children who take Promethazine Hydrochloride and Codeine Phosphate Oral Solution with benzodiazepines, or other central nervous system depressants, including alcohol.
Do not take any benzodiazepines or medicines that can cause d… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Absorption Codeine is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60 minutes post administration. The presence of a high-fat, high-calorie meal did not significantly impact the PK of codeine. Promethazine is well absorbed from the gastrointestinal tract.
Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Distribution Codeine has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. Codeine has low plasma protein binding with about 7 to 25% of codeine bound to plasma proteins.
Codeine passes the blood brain barrier and the placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast milk. Promethazine is widely distributed in body tissues.
Promethazine has high protein binding with about 80 to 93% of promethazine bound to plasma proteins. Promethazine passes the blood brain barrier and the placental barrier. Elimination Metabolism Codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (about 70 to 80%), by O-demethylation to morphine (about 5 to 10%), and by N-demethylation to norcodeine (about 10%).
UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidation 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-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and its M6 glucuronide conjugate are pharmacologically active. Whether C6G has pharmacological activity is unknown.
Norcodeine and M3 glucuronide conjugate of morphine are generally not considered to be pharmacologically active. Promethazine is metabolized by the liver to a variety of inactive metabolites such as sulfoxides of promethazine, N-demethylpromethazine and other glucuronides. Excretion 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 have been reported to be approximately 3 hours. Promethazine has an elimination half-life of 10-14 hours, with excretion of metabolites appearing in the urine and feces. The sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine.
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Codeine Effects on the Central Nervous System Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Codeine causes miosis, even in total darkness.
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.
Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [ see Adverse Reactions (6) ].
They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [ see Adverse Reactions (6) ].
Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration–Adverse Reaction Relationships There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. Promethazine Promethazine competitively antagonize H 1 receptors located in most of the smooth muscle including the gastrointestinal tract, uterus, large blood vessels and bronchial muscle.
Actions of histamine on H 1 receptors increases capillary permeability and edema formation, flare and pruritus.
🔒 Drug Abuse and Dependence ▾
9 DRUG ABUSE AND DEPENDENCE
9.1Controlled Substance Promethazine HCl and Codeine Phosphate Oral Solution contains codeine, a Schedule V controlled substance.
9.2Abuse Codeine Promethazine HCl and Codeine Phosphate Oral Solution contains codeine, a substance with a high potential for abuse similar to other opioids including morphine and codeine. Promethazine HCl and Codeine Phosphate Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions (5.1) ] . All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic and antitussive products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders.
Drug-seeking tactics include emergency calls or visits near the end of office 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 health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Promethazine HCl and Codeine Phosphate Oral Solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of Promethazine HCl and Codeine Phosphate Oral Solution Promethazine HCl and Codeine Phosphate Oral Solution is for oral use only. Abuse of Promethazine HCl and Codeine Phosphate Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Promethazine HCl and Codeine Phosphate Oral Solution with alcohol and other central nervous system depressants [ see Warnings and Precautions (5.10) ].
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
9.3Dependence Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, Promethazine HCl and Codeine Phosphate Oral Solution should be prescribed and administered for the shortest duration that is consistent with individual patient treatment goals and patients should be reevaluated prior to refills [ see Dosage and Administration (2.3) , Warnings and Precautions (5.1) ]. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution; however, published information is available for the individual active ingredients. Codeine Carcinogenicity studies were conducted with codeine. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine.
No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 15 and 20 times, the MRHD on a mg/m 2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 45 times the MRHD on a mg/m 2 basis). Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.
Fertility studies with codeine have not been conducted. Promethazine Carcinogenicity studies were conducted with promethazine hydrochloride. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of promethazine hydrochloride.
No evidence of tumorigenicity was observed in male and female rats at promethazine hydrochloride oral doses up to 33 mg/kg/day for 5 days/week (approximately equivalent to 10 times the MRHD on a mg/m 2 basis). No evidence of tumorigenicity was observed in male and female mice at promethazine hydrochloride oral doses up to 45 and 15 mg/kg/day for 5 days/week (approximately equivalent to 7 and 2 times the MRHD on a mg/m 2 basis, respectively). Promethazine hydrochloride was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.
Fertility studies with promethazine have not been conducted.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution; however, published information is available for the individual active ingredients. Codeine Carcinogenicity studies were conducted with codeine. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine.
No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 15 and 20 times, the MRHD on a mg/m 2 basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 45 times the MRHD on a mg/m 2 basis). Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.
Fertility studies with codeine have not been conducted. Promethazine Carcinogenicity studies were conducted with promethazine hydrochloride. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of promethazine hydrochloride.
No evidence of tumorigenicity was observed in male and female rats at promethazine hydrochloride oral doses up to 33 mg/kg/day for 5 days/week (approximately equivalent to 10 times the MRHD on a mg/m 2 basis). No evidence of tumorigenicity was observed in male and female mice at promethazine hydrochloride oral doses up to 45 and 15 mg/kg/day for 5 days/week (approximately equivalent to 7 and 2 times the MRHD on a mg/m 2 basis, respectively). Promethazine hydrochloride was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.
Fertility studies with promethazine have not been conducted.
📄 Package Label / Principal Display Panel ▾
PRINCIPAL DISPLAY PANEL NDC 0713- 0823 -75 Rx only Promethazine Hydrochloride and Codeine Phosphate Oral Solution CV 6.25 mg and 10 mg per 5 mL Alcohol 8% (v/v) WARNINGS: Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions. PHARMACIST: Dispense the accompanying Medication Guide to each patient. 16 fl. oz. (473 mL) 16 oz label