CODEINE: 21,932 Adverse Event Reports & Safety Profile

Promethazine and phenylephrine HCl and codeine phosphate oral solution, USP contains codeine USP, an opioid agonist; promethazine, a phenothiazine; and phenylephrine, an alpha-1 adrenergic receptor agonist.

Each

5 mL of promethazine and phenylephrine HCl and codeine phosphate oral solution, USP contains 10 mg of codeine phosphate, USP, 6.25 mg of promethazine hydrochloride, USP and 5 mg of phenylephrine hydrochloride, USP for oral administration. Promethazine and phenylephrine HCl and codeine phosphate oral solution, USP contains Alcohol 7.15% v/v. Promethazine and phenylephrine HCl and codeine phosphate oral solution, USP also contains the following inactive ingredients: anhydrous citric acid, ascorbic acid, edetate disodium, glycerin, methylparaben, natural & artificial citrus flavor FN-7176, purified water, saccharin sodium, sodium benzoate, sodium metabisulfite, sodium citrate, and sucrose.

Codeine

Phosphate, USP The chemical name for codeine phosphate, USP is 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Codeine, USP 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, USP occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate, USP 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
• 1/2 H 2 O, and it has the following chemical structure.

Promethazine

Hydrochloride, USP The chemical name for promethazine hydrochloride USP, a phenothiazine derivative, is (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride. Promethazine hydrochloride, USP 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.

Phenylephrine

Hydrochloride, USP The chemical name for phenylephrine hydrochloride USP, a sympathomimetic amine salt, is (-)- m -hydroxy-α-[(methyl-amino)methyl] benzyl alcohol hydrochloride. Phenylephrine hydrochloride, USP occurs as white or nearly white crystals, having a bitter taste. It is freely soluble in water and alcohol. Phenylephrine hydrochloride, USP is subject to oxidation and must be protected from light and air. The molecular weight is 203.67. Its molecular formula is C 9 H 13 NO 2

• HCl, and it has the following chemical structure. 10 11 12

AND USAGE Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold in patients 18 years of age and older. 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, misuse, overdose and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ], reserve Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of cough. Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution is a combination of codeine, an opioid agonist; promethazine, a phenothiazine; and phenylephrine, an alpha-1 adrenergic receptor agonist, indicated for the temporary relief of cough and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold in patients 18 years of age and older. ( 1 ) Limitations of Use Not indicated for pediatric patients under 18 years of age. (1) Because of the risks of addiction, abuse, misuse, overdose, and death which can occur at any dosage or duration and persist over the course of therapy, reserve Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution for use in adult patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of cough. (1 , 5.1)

AND ADMINISTRATION

• Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 )
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 )
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 )
• Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 )
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 )
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Codeine Sulfate Tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 )
• Initiate treatment with 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets. ( 2.3 )
• Periodically reassess patients receiving Codeine Sulfate Tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 )
• Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.16 )

2.1 Important Dosage and Administration Instructions

• Codeine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Codeine Sulfate Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] .
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Codeine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )].

2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]</span>. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent .

2.3 Initial Dosage Initiating Treatment with Codeine Sulfate Tablets: Initiate treatment with Codeine Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Codeine Sulfate Tablets. Adult doses of Codeine Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions. The maximum 24-hour dose is 360 mg. Conversion from Other Opioids to Codeine Sulfate Tablets: There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Codeine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Codeine Sulfate Tablets dosage than to overestimate the 24-hour Codeine Sulfate Tablets dosage and manage an adverse reaction due to overdose.

2.4 Titration and Maintenance of Therapy Individually titrate Codeine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving codeine sulfate to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.16 )]</span> . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Codeine Sulfate Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 )]</span> . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.5 Safe Reduction or Discontinuation of Codeine Sulfate Tablets Do not rapidly reduce or abruptly discontinue Codeine Sulfate Tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Codeine Sulfate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including Codeine Sulfate Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Codeine Sulfate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 )]</span>.

Promethazine and Phenylephrine 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 and Phenylephrine 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) ] . Narrow angle glaucoma, urinary retention, severe hypertension, severe coronary artery disease, or peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds) [see Warnings and Precautions (5.13) ] . A history of an idiosyncratic reaction to promethazine or to other phenothiazines [see Warnings and Precautions (5.15) ] . Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [see Warnings and Precautions (5.17) , Drug Interactions (7.6) ] . Hypersensitivity to codeine, promethazine, phenylephrine, or any of the inactive ingredients in Promethazine and Phenylephrine 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 ) Patients with narrow angle glaucoma, urinary retention, severe hypertension, severe coronary artery disease, or peripheral vascular insufficiency. ( 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, phenylephrine, or any of the inactive ingredients in Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution. ( 4 )

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 )]
• Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.3 )]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )]
• Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 )]
• Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )]
• Severe Hypotension [see Warnings and Precautions ( 5.12 )]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 )]
• Seizures [see Warnings and Precautions ( 5.15 )]
• Withdrawal [see Warnings and Precautions ( 5.16 )] The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions with codeine administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis. Other less frequently observed adverse reactions expected from opioid analgesics, including Codeine Sulfate Tablets, include: Cardiovascular System : faintness, flushing, hypotension, palpitations, syncope Digestive System : abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis Nervous System : anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness Skin and Appendages : rash, sweating, urticaria Serotonin Syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal

Insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Tablets.

Androgen

Deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )] .

Adverse

Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over

12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 ) ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The

5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately

17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 )

5.1 Addiction, 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.

5.2 Life-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 Warnings and Precautions (5.4) ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of Promethazine HCl and Codeine Phosphate Oral Solution, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status [ see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Promethazine HCl and Codeine Phosphate Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with other drugs that may cause respiratory depression [ see Warnings and Precautions (5.10) ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [ see Warnings and Precautions (5.6) ]. To reduce the risk of respiratory depression, proper dosing of Promethazine HCl and Codeine Phosphate Oral Solution is essential [ see Dosage and Administration (2.1) , Warnings and Precautions (5.7) ]. Monitor patients closely, especially within the first 24-72 hours of initiating therapy or when used in patients at higher risk. Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children younger than 12 years of age has been associated with fatal respiratory depression when used as recommended [ see Warnings and Precautions (5.3) ]. Accidental ingestion of even one dose of Promethazine HCl and Codeine Phosphate Oral Solution, especially by children, can result in respiratory depression and death.

5.3 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death: Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in 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. 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 (5.10) , Use in Specific Populations (8.4) ]. Healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [ see Warnings and Precautions (5.1) , Overdosage (10) ] . Lactation At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Promethazine HCl and Codeine Phosphate Oral Solution [ see Use in Specific Populations (8.2) ]. CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [ see Overdosage (10) ]. Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine HCl and Codeine Phosphate Oral Solution.

5.4 Promethazine and Respiratory Depression Children Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients. Concomitant administration with other respiratory depressants may increase the risk of respiratory depression. 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 (5.3 , 5.5 , 5.10) ]. Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death [ see Overdosage (10) ].

Concomitant

Conditions and Other Risk Factors Avoid use of promethazine in patients at risk for respiratory depression. 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 (5.6 , 5.10 )] .

5.5 Risks with Use in Pediatric Populations Children are particularly sensitive to the respiratory depressant effects of codeine [ see Warnings and Precautions (5.2 , 5.3) ] and 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 in children less than 12 years of age, and in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ]. Use of Promethazine HCl and Codeine Phosphate Oral Solution in children also exposes them to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence (9) ], which can lead to overdose and death [ see Warnings and Precautions (5.1), Overdosage (10) ]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of codeine in pediatric patients, Promethazine HCl and Codeine Phosphate Oral Solution is not indicated for use in patients younger than 18 years of age [ see Indications (1) , Use in Specific Populations (8.4) ].

5.6 Risks with Use in Other At-Risk Populations Unresponsive Cough 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 in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Dosage and Administration (2.3) ]. Asthma and Other Pulmonary Disease The use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [ see Contraindications (4) ]. Opioid analgesics and antitussives, including codeine, one of the active ingredients in Promethazine HCl and Codeine Phosphate Oral Solution, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. Promethazine HCl and Codeine Phosphate Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Promethazine HCl and Codeine Phosphate Oral Solution [ see Warnings and Precautions (5.2) ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [ see Warnings and Precautions (5.2) ]. Because of the risk of respiratory depression, avoid the use of opioid antitussives, including Promethazine HCl and Codeine Phosphate Oral Solution in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients.

If

Promethazine HCl and Codeine Phosphate Oral Solution is prescribed, monitor such patients closely, particularly when initiating Promethazine HCl and Codeine Phosphate Oral Solution and when Promethazine HCl and Codeine Phosphate Oral Solution is given concomitantly with other drugs that depress respiration [ see Warnings and Precautions (5.10) ].

5.7 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Promethazine HCl and Codeine Phosphate Oral Solution is communicated clearly and dispensed accurately [ see Dosage and Administration (2.1) ]. Advise patients to always use an accurate milliliter measuring device when measuring and administering Promethazine HCl and Codeine Phosphate Oral Solution. Inform patients that a household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ see Overdosage (10) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery Codeine and promethazine, two of the active ingredients in Promethazine HCl and Codeine Phosphate Oral Solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Promethazine HCl and Codeine Phosphate Oral Solution. Avoid concurrent use of Promethazine HCl and Codeine Phosphate Oral Solution with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [ see Warnings and Precautions (5.10) ].

5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Promethazine HCl and Codeine Phosphate Oral Solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with inhibitors and inducers of CYP3A4 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.1, 7.2) ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking a CYP2D6 inhibitor. If concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with inhibitors of CYP2D6 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.3) ].

5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including Promethazine HCl and Codeine Phosphate Oral Solution, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [ see Drug Interactions (7.4) ]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if Promethazine HCl and Codeine Phosphate Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants [ see Patient Counseling Information (17) ].

5.11 Risks of Use in Patients with Gastrointestinal Conditions Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [ see Contraindications (4) ]. The use of codeine in Promethazine HCl and Codeine Phosphate Oral Solution may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with Promethazine HCl and Codeine Phosphate Oral Solution may produce paralytic ileus [ see Drug Interactions (7.9) ]. The codeine in Promethazine HCl and Codeine Phosphate Oral Solution may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders. The codeine in Promethazine HCl and Codeine Phosphate Oral Solution may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [ see Warnings and Precautions (5.21) ]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Administration of promethazine has been associated with reported cholestatic jaundice.

5.12 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Promethazine HCl and Codeine Phosphate Oral Solution may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.13 Risk of Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, avoid use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with a history consistent with NMS.

5.14 Risk of Paradoxical Reactions, including Dystonias Promethazine HCl and Codeine Phosphate Oral Solution contains promethazine, a phenothiazine. Phenothiazines are associated with dystonic reactions, particularly in pediatric patients who have an acute illness associated with dehydration. Paradoxical reactions, including dystonia, torticollis, tongue protrusion, hyperexcitability, and abnormal movements have been reported in patients following a single administration of promethazine.

Discontinue

Promethazine HCl and Codeine Phosphate Oral Solution if a paradoxical reaction occurs.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders The codeine and promethazine in Promethazine HCl and Codeine Phosphate Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Promethazine HCl and Codeine Phosphate Oral Solution therapy.

5.16 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) Concurrent use of Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such therapy [ see Contraindications (4) ]. MAOIs may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion MAOIs [ see Drug Interactions (7.6) ].

5.17 Bone-Marrow Depression Promethazine HCl and Codeine Phosphate Oral Solution should be used with caution in patients with bonemarrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine has been used in association with other known marrow-toxic agents.

5.18 Severe Hypotension Promethazine HCl and Codeine Phosphate Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [ see Drug Interactions (7.4) ]. Monitor these patients for signs of hypotension after initiating Promethazine HCl and Codeine Phosphate Oral Solution. In patients with circulatory shock, Promethazine HCl and Codeine Phosphate Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with circulatory shock.

5.19 Neonatal Opioid Withdrawal Syndrome Promethazine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women. Prolonged use of Promethazine HCl and Codeine Phosphate Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations (8.1) , Patient Counseling Information (17) ].

5.20 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.21 Drug/Laboratory Test Interactions Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of Promethazine HCl and Codeine Phosphate Oral Solution. The following laboratory tests may be affected in patients who are receiving promethazine: Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance

Test: An increase in blood glucose has been reported in patients receiving promethazine.

5.1 Addiction, 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.

5.2 Life-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 Warnings and Precautions (5.4) ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of Promethazine HCl and Codeine Phosphate Oral Solution, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status [ see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Promethazine HCl and Codeine Phosphate Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with other drugs that may cause respiratory depression [ see Warnings and Precautions (5.10) ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [ see Warnings and Precautions (5.6) ]. To reduce the risk of respiratory depression, proper dosing of Promethazine HCl and Codeine Phosphate Oral Solution is essential [ see Dosage and Administration (2.1) , Warnings and Precautions (5.7) ]. Monitor patients closely, especially within the first 24-72 hours of initiating therapy or when used in patients at higher risk. Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children younger than 12 years of age has been associated with fatal respiratory depression when used as recommended [ see Warnings and Precautions (5.3) ]. Accidental ingestion of even one dose of Promethazine HCl and Codeine Phosphate Oral Solution, especially by children, can result in respiratory depression and death.

5.3 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death: Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in 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. 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 (5.10) , Use in Specific Populations (8.4) ]. Healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [ see Warnings and Precautions (5.1) , Overdosage (10) ] . Lactation At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Promethazine HCl and Codeine Phosphate Oral Solution [ see Use in Specific Populations (8.2) ]. CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [ see Overdosage (10) ]. Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine HCl and Codeine Phosphate Oral Solution.

5.4 Promethazine and Respiratory Depression Children Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients. Concomitant administration with other respiratory depressants may increase the risk of respiratory depression. 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 (5.3 , 5.5 , 5.10) ]. Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death [ see Overdosage (10) ].

Concomitant

Conditions and Other Risk Factors Avoid use of promethazine in patients at risk for respiratory depression. 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 (5.6 , 5.10 )] .

5.5 Risks with Use in Pediatric Populations Children are particularly sensitive to the respiratory depressant effects of codeine [ see Warnings and Precautions (5.2 , 5.3) ] and 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 in children less than 12 years of age, and in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ]. Use of Promethazine HCl and Codeine Phosphate Oral Solution in children also exposes them to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence (9) ], which can lead to overdose and death [ see Warnings and Precautions (5.1), Overdosage (10) ]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of codeine in pediatric patients, Promethazine HCl and Codeine Phosphate Oral Solution is not indicated for use in patients younger than 18 years of age [ see Indications (1) , Use in Specific Populations (8.4) ].

5.6 Risks with Use in Other At-Risk Populations Unresponsive Cough 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 in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Dosage and Administration (2.3) ]. Asthma and Other Pulmonary Disease The use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [ see Contraindications (4) ]. Opioid analgesics and antitussives, including codeine, one of the active ingredients in Promethazine HCl and Codeine Phosphate Oral Solution, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. Promethazine HCl and Codeine Phosphate Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Promethazine HCl and Codeine Phosphate Oral Solution [ see Warnings and Precautions (5.2) ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [ see Warnings and Precautions (5.2) ]. Because of the risk of respiratory depression, avoid the use of opioid antitussives, including Promethazine HCl and Codeine Phosphate Oral Solution in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients.

If

Promethazine HCl and Codeine Phosphate Oral Solution is prescribed, monitor such patients closely, particularly when initiating Promethazine HCl and Codeine Phosphate Oral Solution and when Promethazine HCl and Codeine Phosphate Oral Solution is given concomitantly with other drugs that depress respiration [ see Warnings and Precautions (5.10) ].

5.7 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Promethazine HCl and Codeine Phosphate Oral Solution is communicated clearly and dispensed accurately [ see Dosage and Administration (2.1) ]. Advise patients to always use an accurate milliliter measuring device when measuring and administering Promethazine HCl and Codeine Phosphate Oral Solution. Inform patients that a household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ see Overdosage (10) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery Codeine and promethazine, two of the active ingredients in Promethazine HCl and Codeine Phosphate Oral Solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Promethazine HCl and Codeine Phosphate Oral Solution. Avoid concurrent use of Promethazine HCl and Codeine Phosphate Oral Solution with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [ see Warnings and Precautions (5.10) ].

5.9 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Promethazine HCl and Codeine Phosphate Oral Solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with inhibitors and inducers of CYP3A4 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.1, 7.2) ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking a CYP2D6 inhibitor. If concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with inhibitors of CYP2D6 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.3) ].

5.10 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including Promethazine HCl and Codeine Phosphate Oral Solution, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [ see Drug Interactions (7.4) ]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if Promethazine HCl and Codeine Phosphate Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants [ see Patient Counseling Information (17) ].

5.11 Risks of Use in Patients with Gastrointestinal Conditions Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [ see Contraindications (4) ]. The use of codeine in Promethazine HCl and Codeine Phosphate Oral Solution may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with Promethazine HCl and Codeine Phosphate Oral Solution may produce paralytic ileus [ see Drug Interactions (7.9) ]. The codeine in Promethazine HCl and Codeine Phosphate Oral Solution may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders. The codeine in Promethazine HCl and Codeine Phosphate Oral Solution may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [ see Warnings and Precautions (5.21) ]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Administration of promethazine has been associated with reported cholestatic jaundice.

5.12 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Promethazine HCl and Codeine Phosphate Oral Solution may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.13 Risk of Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, avoid use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with a history consistent with NMS.

5.14 Risk of Paradoxical Reactions, including Dystonias Promethazine HCl and Codeine Phosphate Oral Solution contains promethazine, a phenothiazine. Phenothiazines are associated with dystonic reactions, particularly in pediatric patients who have an acute illness associated with dehydration. Paradoxical reactions, including dystonia, torticollis, tongue protrusion, hyperexcitability, and abnormal movements have been reported in patients following a single administration of promethazine.

Discontinue

Promethazine HCl and Codeine Phosphate Oral Solution if a paradoxical reaction occurs.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders The codeine and promethazine in Promethazine HCl and Codeine Phosphate Oral Solution may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Promethazine HCl and Codeine Phosphate Oral Solution therapy.

5.16 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) Concurrent use of Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such therapy [ see Contraindications (4) ]. MAOIs may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion MAOIs [ see Drug Interactions (7.6) ].

5.17 Bone-Marrow Depression Promethazine HCl and Codeine Phosphate Oral Solution should be used with caution in patients with bonemarrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine has been used in association with other known marrow-toxic agents.

5.18 Severe Hypotension Promethazine HCl and Codeine Phosphate Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [ see Drug Interactions (7.4) ]. Monitor these patients for signs of hypotension after initiating Promethazine HCl and Codeine Phosphate Oral Solution. In patients with circulatory shock, Promethazine HCl and Codeine Phosphate Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients with circulatory shock.

5.19 Neonatal Opioid Withdrawal Syndrome Promethazine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women. Prolonged use of Promethazine HCl and Codeine Phosphate Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations (8.1) , Patient Counseling Information (17) ].

5.20 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.21 Drug/Laboratory Test Interactions Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of Promethazine HCl and Codeine Phosphate Oral Solution. The following laboratory tests may be affected in patients who are receiving promethazine: Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.

Glucose Tolerance

Test: An increase in blood glucose has been reported in patients receiving promethazine.

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 )

7.1 Inhibitors 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.

7.2 CYP3A4 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.

7.3 Inhibitors 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.

7.4 Benzodiazepines, 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, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking benzodiazepines or other CNS depressants. [ see Warnings and Precautions (5.10) ].

7.5 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation.

Discontinue

Promethazine HCl and Codeine Phosphate Oral Solution if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs) Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients who are taking MAOIs (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease) or have taken MAOIs within 14 days [ see Contraindications (4) ]. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions (5.16) ]. Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

7.7 Muscle Relaxants Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic Drugs The concomitant use of anticholinergic drugs with Promethazine HCl and Codeine Phosphate Oral Solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions (5.11) ]. Monitor patients for signs of urinary retention or reduced gastric motility when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with promethazine].

7.1 Inhibitors 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.

7.2 CYP3A4 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.

7.3 Inhibitors 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.

7.4 Benzodiazepines, 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, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking benzodiazepines or other CNS depressants. [ see Warnings and Precautions (5.10) ].

7.5 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation.

Discontinue

Promethazine HCl and Codeine Phosphate Oral Solution if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs) Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients who are taking MAOIs (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease) or have taken MAOIs within 14 days [ see Contraindications (4) ]. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions (5.16) ]. Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

7.7 Muscle Relaxants Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic Drugs The concomitant use of anticholinergic drugs with Promethazine HCl and Codeine Phosphate Oral Solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions (5.11) ]. Monitor patients for signs of urinary retention or reduced gastric motility when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with promethazine].

Active Ingredients(in each 5 ml tsp.)

Purpose Codeine

Phosphate ................................................. 10 mg ..........

Cough Suppressant

Guaifenesin .......................................................... 100 mg ..................

Expectorant

Pseudoephedrine HCl ............................................. 30 mg ..........

Nasal

Decongestant

Inactive ingredients Citric acid, edetate disodium, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, flavor, glycerin, menthol, propylene glycol, purified water, sodium benzoate, sodium citrate, sodium saccharin and sorbitol.