Phenergan VC Expectorant with Codeine

Codeine Phosphate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Medication guide
• Phenergan VC Expectorant with Codeine (Codeine Phosphate) reviews

1 INDICATIONS AND USAGE

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses , reserve Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate. (1)

Limitations of Use (1)

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

2 DOSAGE AND ADMINISTRATION

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
• Initiate treatment with 15 to 60 mg every 4 hours as needed. (2.2)
• Do not stop Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets abruptly in a physically dependent patient. (2.4)

2.1 Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals .

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse .

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets and adjust the dosage accordingly .

2.2 Initial Dosage

Initiating Treatment with Phenergan VC Expectorant with Codeine Sulfate Tablets

Initiate treatment with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain.

Adult doses of Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage than to overestimate the 24-hour Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage and manage an adverse reaction due to overdose.

2.3 Titration and Maintenance of Therapy

Individually titrate Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Phenergan VC Expectorant with Codeine Sulfate Tablets

When a patient who has been taking Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets regularly and may be physically dependent no longer requires therapy with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient .

3 DOSAGE FORMS AND STRENGTHS

Each 15 mg tablet for oral administration contains 15 mg of Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “15” debossed on the scored side and “54 613” debossed on the other side.

Each 30 mg tablet for oral administration contains 30 mg of Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “30” debossed on the scored side and “54 783” debossed on the other side.

Each 60 mg tablet for oral administration contains 60 mg of Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate USP. It is a white to off-white biconvex tablet with “60” debossed on the scored side and “54 412” debossed on the other side.

Tablets: 15 mg, 30 mg, and 60 mg (3)

4 CONTRAINDICATIONS

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated for:

• All children younger than 12 years of age .
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy .

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are also contraindicated in patients with:

• Significant respiratory depression .
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment .
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days .
• Known or suspected gastrointestinal obstruction, including paralytic ileus .
• Hypersensitivity to Phenergan VC Expectorant with Codeine (Codeine Phosphate) (e.g., anaphylaxis) .

• Children younger than 12 years of age.
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4)
• Significant respiratory depression. (4)
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
• Hypersensitivity to Phenergan VC Expectorant with Codeine (Codeine Phosphate). (4)

5 WARNINGS AND PRECAUTIONS

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in patients with circulatory shock. (5.10)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets contain Phenergan VC Expectorant with Codeine (Codeine Phosphate), a Schedule II controlled substance. As an opioid, Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets exposes users to the risks of addiction, abuse, and misuse .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, and monitor all patients receiving Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets for the development of these behaviors and conditions. 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). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. 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 . 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, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status . Carbon dioxide (CO₂) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are essential . Overestimating the Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of Phenergan VC Expectorant with Codeine (Codeine Phosphate).

5.3 Ultra-Rapid Metabolism of Phenergan VC Expectorant with Codeine (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received Phenergan VC Expectorant with Codeine (Codeine Phosphate). Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate), 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate). Furthermore, children with obstructive sleep apnea who are treated with Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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:

• Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy .
• Avoid the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate) unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
• As with adults, when prescribing Phenergan VC Expectorant with Codeine (Codeine Phosphate) for adolescents, 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 .

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of Phenergan VC Expectorant with Codeine (Codeine Phosphate). Breastfeeding is not recommended during treatment with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets .

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 racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

These individuals convert Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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) . Therefore, individuals who are ultra-rapid metabolizers should not use Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

5.4 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Phenergan VC Expectorant with Codeine Sulfate Tablets 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.

5.5 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets requires careful consideration of the effects on the parent drug, Phenergan VC Expectorant with Codeine (Codeine Phosphate), and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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. Follow patients receiving Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are used in conjunction with inhibitors and inducers of CYP3A4.

If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal [Drug Interactions (7)].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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.

Follow patients receiving Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are used in conjunction with inhibitors of CYP2D6.

If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets dosage and follow the patient for signs and symptoms of respiratory depression or sedation .

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Phenergan VC Expectorant with Codeine Sulfate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs .

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets-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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets .

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 .

Monitor such patients closely, particularly when initiating and titrating Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets and when Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are given concomitantly with other drugs that depress respiration . Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment .

5.9 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.

5.10 Severe Hypotension

Phenergan VC Expectorant with Codeine Sulfate Tablets 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) . Monitor these patients for signs of hypotension after initiating or titrating the dosage of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. In patients with circulatory shock, Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in patients with circulatory shock.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Phenergan VC Expectorant with Codeine Sulfate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The Phenergan VC Expectorant with Codeine (Codeine Phosphate) in Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The Phenergan VC Expectorant with Codeine (Codeine Phosphate) in Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets therapy.

5.14 Withdrawal

Avoid the use of mixed agonist/antagonist or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms .

When discontinuing Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient, gradually taper the dosage . Do not abruptly discontinue Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in these patients .

5.15 Risks of Driving and Operating Machinery

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets and know how they will react to the medication .

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse
• Life-Threatening Respiratory Depression
• Ultra-Rapid Metabolism of Phenergan VC Expectorant with Codeine (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Benzodiazepines and Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal
  

  The following adverse reactions associated with the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
  

The most frequently observed adverse reactions with Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) 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 Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids .

The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate if serotonin syndrome is suspected. (7)
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets because they may reduce analgesic effect of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets or precipitate withdrawal symptoms. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: May cause fetal harm.
• Lactation: Breastfeeding not recommended. (8.2)

8.1 Pregnancy

Pregnancy Category C

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome . Available data with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Phenergan VC Expectorant with Codeine (Codeine Phosphate) administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [see Data ].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

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

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly .

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data: Studies on the reproductive and developmental effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate) have been reported in the published literature in hamsters, rats, mice and rabbits.

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of Phenergan VC Expectorant with Codeine (Codeine Phosphate) (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg² basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) of Phenergan VC Expectorant with Codeine (Codeine Phosphate) during organogenesis.

Phenergan VC Expectorant with Codeine (Codeine Phosphate) (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.

8.2 Lactation

Risk Summary

Phenergan VC Expectorant with Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to Phenergan VC Expectorant with Codeine (Codeine Phosphate) via breast milk. Women who are ultra-rapid metabolizers of Phenergan VC Expectorant with Codeine (Codeine Phosphate) achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal Phenergan VC Expectorant with Codeine (Codeine Phosphate) metabolism (normal CYP2D6 activity), the amount of Phenergan VC Expectorant with Codeine (Codeine Phosphate) secreted into human milk is low and dose-dependent.

There is no information on the effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate) on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets [see Warnings and Precautions (5.3)].

Clinical Considerations

If infants are exposed to Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible .

8.4 Pediatric Use

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

Life-threatening respiratory depression and death have occurred in children who received Phenergan VC Expectorant with Codeine (Codeine Phosphate) . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of Phenergan VC Expectorant with Codeine (Codeine Phosphate) (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate). Because of the risk of life-threatening respiratory depression and death:

• Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
• Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy .
• Avoid the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of Phenergan VC Expectorant with Codeine (Codeine Phosphate) unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression .

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to Phenergan VC Expectorant with Codeine (Codeine Phosphate). In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression .

Phenergan VC Expectorant with Codeine (Codeine Phosphate) is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of Phenergan VC Expectorant with Codeine in this patient population are unknown. Start these patients with a lower than normal dosage of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

8.7 Renal Impairment

Phenergan VC Expectorant with Codeine (Codeine Phosphate) pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients with a lower than normal dosage of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Phenergan VC Expectorant with Codeine Sulfate Tablets contain Phenergan VC Expectorant with Codeine (Codeine Phosphate), a Schedule II controlled substance.

9.2 Abuse

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets contains Phenergan VC Expectorant with Codeine (Codeine Phosphate), a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets can be abused and is subject to misuse, addiction, and criminal diversion .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

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

Risks Specific to Abuse of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are for oral use only. Abuse of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infection diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets should not be abruptly discontinued in a physically-dependent patient . If Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs .

10 OVERDOSAGE

Clinical Presentation

Acute overdose with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations .

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to Phenergan VC Expectorant with Codeine (Codeine Phosphate) overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Phenergan VC Expectorant with Codeine (Codeine Phosphate) overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of Phenergan VC Expectorant with Codeine (Codeine Phosphate) in Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets USP contain Phenergan VC Expectorant with Codeine (Codeine Phosphate), an opioid agonist, available for oral administration containing either 15 mg, 30 mg, or 60 mg of Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate USP. The chemical name is morphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-(5α,6α)-, sulfate (2:1) (salt), trihydrate. Its molecular formula is (C₁₈H₂₁NO₃)₂ - H₂SO₄ - 3H₂O and its molecular weight is 750.85 g/mol.

Its structure is as follows:

Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate trihydrate is a fine, white, crystalline powder which is soluble in water and insoluble in chloroform and ether.

The inactive ingredients in Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets USP include: colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch and stearic acid.

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Phenergan VC Expectorant with Codeine sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of Phenergan VC Expectorant with Codeine (Codeine Phosphate) have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Phenergan VC Expectorant with Codeine (Codeine Phosphate) produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Phenergan VC Expectorant with Codeine (Codeine Phosphate) causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Phenergan VC Expectorant with Codeine (Codeine Phosphate) causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Phenergan VC Expectorant with Codeine (Codeine Phosphate) produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of Phenergan VC Expectorant with Codeine (Codeine Phosphate) for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance .

Concentration–Adverse Reaction Relationships

There is a relationship between increasing Phenergan VC Expectorant with Codeine (Codeine Phosphate) plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions .

12.3 Pharmacokinetics

Absorption

Phenergan VC Expectorant with Codeine (Codeine Phosphate) is absorbed from the gastrointestinal tract with maximum plasma concentration occurring 60 minutes post administration. Administration of 15 mg of Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate every four hours for 5 days resulted in steady-state concentrations of Phenergan VC Expectorant with Codeine (Codeine Phosphate), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours.

Food Effect: When 60 mg Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate was administered 30 minutes after ingesting a high fat/high calorie meal, there was no significant change in the rate and extent of absorption of Phenergan VC Expectorant with Codeine (Codeine Phosphate).

Distribution

Phenergan VC Expectorant with Codeine (Codeine Phosphate) has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. Phenergan VC Expectorant with Codeine (Codeine Phosphate) has low plasma protein binding with about 7% to 25% of Phenergan VC Expectorant with Codeine (Codeine Phosphate) bound to plasma proteins.

Elimination

Phenergan VC Expectorant with Codeine (Codeine Phosphate) is metabolized by conjugation to codeine-6-glucuronide (70% to 80%), by O-demethylation to morphine (5% to 10%), and by N-demethylation to norcodeine (~10%). Approximately 90% of the total dose of Phenergan VC Expectorant with Codeine (Codeine Phosphate) is excreted through the kidneys. The plasma half-lives of Phenergan VC Expectorant with Codeine (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

Metabolism: About 70% to 80% of the administered dose of Phenergan VC Expectorant with Codeine (Codeine Phosphate) is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5% to 10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of Phenergan VC Expectorant with Codeine (Codeine Phosphate) to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of Phenergan VC Expectorant with Codeine (Codeine Phosphate) to morphine and P450 3A4 is the major enzyme mediating conversion of Phenergan VC Expectorant with Codeine (Codeine Phosphate) to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties.

Excretion: Approximately 90% of the total dose of Phenergan VC Expectorant with Codeine (Codeine Phosphate) is excreted through the kidneys, of which approximately 10% is unchanged Phenergan VC Expectorant with Codeine (Codeine Phosphate). Plasma half-lives of Phenergan VC Expectorant with Codeine (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of Phenergan VC Expectorant with Codeine (Codeine Phosphate) (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of Phenergan VC Expectorant with Codeine (Codeine Phosphate) (approximately 5 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) for two years.

Mutagenesis

Phenergan VC Expectorant with Codeine (Codeine Phosphate) was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

Impairment of Fertility

No animal studies were conducted to evaluate the effect of Phenergan VC Expectorant with Codeine (Codeine Phosphate) on male or female fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets USP

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

NDC 0054-0243-24: 100 (4 blister packs per carton x 25 tablets per blister pack) Unit-Dose Tablets

30 mg tablet: supplied as white to off-white biconvex tablets with “30” debossed on the scored side and “54 783” debossed on the other side.

NDC 0054-0244-24: 100 (4 blister packs per carton x 25 tablets per blister pack) Unit-Dose Tablets

NDC 0054-0244-25: Bottle of 100 Tablets

60 mg tablet: supplied as white to off-white biconvex tablets with “60” debossed on the scored side and “54 412” debossed on the other side.

NDC 0054-0245-25: Bottle of 100 Tablets

Storage

Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F).

Protect from moisture.

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

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death . Instruct patients not to share Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets with others and to take steps to protect Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets or when the dosage is increased, and that it can occur even at recommended dosages . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death .

Instruct patients to take steps to store Phenergan VC Expectorant with Codeine (Codeine Phosphate) sulfate securely and to properly dispose of unused Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets in accordance with the local state guidelines and/or regulations.

Ultra-Rapid Phenergan VC Expectorant with Codeine (Codeine Phosphate) Metabolism of Phenergan VC Expectorant with Codeine (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Advise caregivers that Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets to monitor for signs of respiratory depression .

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider .

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications .

MAOI Interaction

Inform patients not to take Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets .

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms .

Important Administration Instructions

Instruct patients how to properly take Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets.

• Advise patients not to adjust the dose of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets without consulting a physician or other healthcare professional.
• If patients have been receiving treatment with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication .

Hypotension

Inform patients that Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) .

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. Advise patients how to recognize such a reaction and when to seek medical attention .

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated .

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy .

Lactation

Advise women that breastfeeding is not recommended during treatment with Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication .

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention .

Disposal of Unused Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets

Advise patients to properly dispose of unused Phenergan VC Expectorant with Codeine (Codeine Phosphate) Sulfate Tablets. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.

• Distr. by West-Ward
• Pharmaceuticals Corp.
• Eatontown, NJ 07724
• 10005657/10
• Revised August 2017

Medication Guide

10005657/10

Revised August 2017

carton-15mg-tab-07.jpg

Phenylephrine Hydrochloride:

• Drug facts
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions? comments?
• Product packaging
• Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) reviews

Drug Facts

Active ingredients

(in each tablet)

Dexbrompheniramine Maleate 2 mg

Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) Hydrochloride 10 mg

Purpose

Antihistamine

Nasal Decongestant

Uses

Temporarily relieves these symptoms due to the common cold, hay fever (allergic rhinitis) or other upper respiratory allergies:

• runny nose
• sneezing
• itching of the nose or throat
• itchy, watery eyes
• nasal congestion
• reduces swelling of nasal passages

Warnings

Do not exceed recommended dosage.

Do not use this product

• if you are now taking a prescription monoamine oxidase inhibitor (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.
  

Ask a doctor before use if you have

• a breathing problem such as emphysema or chronic bronchitis
• glaucoma
• trouble urinating due to enlargement of the prostate gland
• heart disease
• high blood pressure
• thyroid disease
• diabetes
  

Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers.

When using this product

• excitability may occur, especially in children
• may cause drowsiness
• avoid alcoholic drinks
• alcohol, sedatives, and tranquilizers may increase the drowsiness effect
• use caution when driving a motor vehicle or operating machinery
  

Stop use and ask a doctor if

• nervousness, dizziness, or sleeplessness occur
• symptoms do not improve within 7 days or are accompanied by fever
  

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

Other information

Store at 15° - 30°C (59° - 86°F). Supplied in a tight, light-resistant container with a child-resistant cap. Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) Tablets are dark purple, caplet-shaped, scored tablets, debossed "Poly" bisect "782" on one side and plain on the other.

Inactive ingredients

colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 aluminum lake, dibasic calcium phosphate dihydrate, FD &C Blue #1 aluminum lake, magnesium stearate, and silicified microcrystalline cellulose.

Questions? Comments?

Call1-800-882-1041

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355 Rev. 02/12

Product Packaging

The packaging below represents the labeling currently used.

Principal display panel and side panel for 60 tablets label:

NDC 50991-782-60

Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride)

Tablets

Antihistamine - Nasal Decongestant

Each tablet contains:

Dexbrompheniramine Maleate...2 mg

Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) Hydrochloride...10 mg

60 Tablets

Usual

Dosage: See product foldout for full prescribing information.

Tamper evident by foil seal under cap. Do not use if foil seal is

broken or missing.

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN.

Store at controlled room temperature between 15°-30°C (59°-86°F).

Manufactured for:

Poly Pharmaceuticals

Quitman, MS 39355

Rev. 02/12

Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) Tablets Packaging Phenergan VC Expectorant with Codeine (Phenylephrine Hydrochloride) Tablets Packaging

Promethazine Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Use in pediatric patients
• Other considerations
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) reviews

INDICATIONS AND USAGE

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with codeine syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

CONTRAINDICATIONS

The combination of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population.

Codeine is contraindicated in patients with a known hypersensitivity to the drug.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) or to other phenothiazines.

Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.

WARNINGS

WARNING:

The combination of Phenergan VC Expectorant with Codeine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride have resulted in respiratory depression in these patients.

Codeine:

Dosage of codeine 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.

Codeine may cause or aggravate constipation.

Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.

Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children.

Head Injury And Increased Intracranial Pressure:

The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a pre-existing increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.

Asthma And Other Respiratory Conditions:

Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients. Nor should they be used in acute febrile illness associated with productive cough or in 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.

Hypotensive Effect:

Codeine may produce orthostatic hypotension in ambulatory patients.

Phenergan VC Expectorant with Codeine :

CNS Depression –

Phenergan VC Expectorant with Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should either be eliminated or given in reduced dosage in the presence of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl (see PRECAUTIONS - Information For Patients and Drug Interactions ).

Respiratory Depression –

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) may lead to potentially fatal respiratory depression.

Use of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.

Lower Seizure Threshold –

Phenergan VC Expectorant with Codeine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression –

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) should be used with caution in patients with bone marrow depression. Leukopenia and agranulocytosis have been reported, usually when Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome –

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) 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 Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) 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, the reintroduction of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl should be carefully considered.

Use In Pediatric Patients

The combination of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration.

Excessively large dosages of antihistamines, including Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE ). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl.

Other Considerations

Administration of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) has been associated with reported cholestatic jaundice.

PRECAUTIONS

Animal reproduction studies have not been conducted with the drug combination-promethazine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenergan VC Expectorant with Codeine hydrochloride and codeine phosphate should be given to a pregnant woman only if clearly needed.

General:

Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients.

Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Ultra-Rapid Metabolizers of Codeine

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. 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 experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1–10% in Caucasians, 3% in African Americans, and 16–28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose.

Information For Patients:

Patients should be advised to measure Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with codeine syrup with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

The concomitant use of alcohol or other central-nervous-system depressants, such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers may enhance impairment and should be avoided or their dosage reduced (see WARNINGS -CNS Depression and PRECAUTIONS-Drug Interactions ).

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

Drug Interactions:

Codeine:

In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.

Phenergan VC Expectorant with Codeine :

CNS Depressants –

Phenergan VC Expectorant with Codeine may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl. When given concomitantly with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride), the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.

Epinephrine –

Because of the potential for Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) overdose.

Anticholinergics –

Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors –

Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

Drug/Laboratory Test Interactions:

Because narcotic analgesics may increase biliary tract pressure with resultant increases in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given.

The following laboratory tests may be affected in patients who are receiving therapy with Phenergan VC Expectorant with Codeine hydrochloride.

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 Phenergan VC Expectorant with Codeine.

Carcinogenesis, Mutagenesis, Impairment Of Fertility:

Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride), nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the Salmonella assay. Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) was nonmutagenic in the Salmonella test system of Ames.

Pregnancy:

Teratogenic Effects - Pregnancy Category C.

Codeine:

A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120-mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no studies in humans, and the significance of these findings to humans, if any, is not known.

Phenergan VC Expectorant with Codeine :

Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) in pregnant women.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects -

Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life.

Phenergan VC Expectorant with Codeine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

Labor And Delivery:

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE ).

Limited data suggest that use of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn.

The effect of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and/or codeine on the later growth and development of the newborn is unknown.

Nursing Mothers:

It is not known whether Phenergan VC Expectorant with Codeine is excreted in human milk.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1–10% in Caucasians, 3% in African Americans, and 16–28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS – General - Ultra-Rapid Metabolizers of Codeine ).

Caution should be exercised when Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with codeine syrup is administered to a nursing woman.

Pediatric Use:

The combination of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population (see WARNINGS – Box Warning and Use In Pediatric Patients).

The combination of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate should be used with caution in pediatric patients 6 years and older (see Warnings-Use in Pediatric Patients ).

Geriatric Use:

Clinical studies of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate syrup did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with codeine syrup and observed closely.

ADVERSE REACTIONS

Codeine:

Nervous System – CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, transient hallucination, disorientation, visual disturbances, and convulsions.

Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics).

Gastrointestinal – Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported.

Genitourinary – Oliguria, urinary retention; antidiuretic effect has been reported (common to narcotic analgesics).

Allergic – Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema.

Other – Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride):

Central Nervous System – Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness; confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported.

Cardiovascular – Increased or decreased blood pressure, tachycardia, bradycardia, faintness.

Dermatologic – Dermatitis, photosensitivity, urticaria.

Hematologic – Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis.

Gastrointestinal – Dry mouth, nausea, vomiting, jaundice.

Respiratory – Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal). (See WARNINGS - Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride); Respiratory Depression.)

Other – Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported. (See WARNINGS - Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride); Neuroleptic Malignant Syndrome.)

Paradoxical Reactions – Hyperexcitability and abnormal movements have been reported in patients following a single administration of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCI. Consideration should be given to the discontinuation of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl and to the use of other drugs if these reactions occur. Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients.

DRUG ABUSE AND DEPENDENCE

Controlled Substance:

Phenergan VC Expectorant with Codeine with codeine syrup is a Schedule V Controlled Substance.

Abuse:

Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only under close supervision to patients with a history of drug abuse or dependence.

Dependence:

Psychological dependence, physical dependence, and tolerance are known to occur with codeine.

OVERDOSAGE

Codeine:

Serious overdose with codeine is characterized by respiratory depression, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils, and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) is additive to the depressant effects of codeine.

It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates.

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride):

Signs and symptoms of overdosage with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms – dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms may occur.

Treatment:

The treatment of overdosage with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) and codeine; any depressant effects of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) are not reversed with naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy.

Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.

Limited experience with dialysis indicates that it is not helpful.

DOSAGE AND ADMINISTRATION

The combination of Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population.

It is important that Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with codeine syrup is measured with an accurate measuring device (see PRECAUTIONS-Information For Patients ). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.

The average effective dose for adults and children 12 years of age and over is: 1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

The average effective dose for children 6 years to under 12 years of age is 1/2 to 1 teaspoonful (2.5 mL to 5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

HOW SUPPLIED

Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) with Codeine Syrup, a clear purple syrup with odor of grape menthol, contains Phenergan VC Expectorant with Codeine (Promethazine Hydrochloride) hydrochloride 6.25 mg/5 mL, codeine phosphate 10 mg/5 mL and alcohol 7 percent, and is available in 4 fluid ounce (118 mL), 8 fluid ounce (237 mL) and pint (473 mL).

Store at 20°-25°C (68°-77°F).

Dispense in a tight, light-resistant container with a child-resistant closure as defined in the USP.

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8181652

R1/09-R4