Codral Tension Headache

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Codral Tension Headache uses

Codral Tension Headache consists of Acetaminophen, Codeine Phosphate, Doxylamine Succinate.

Acetaminophen:


Pharmacological action

Codral Tension Headache is an analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, the predominant influence on the thermoregulation center in the hypothalamus, enhances heat transfer.

Why is Codral Tension Headache (Acetaminophen) prescribed?

Pain weak and moderate intensity of different genesis (including headache, migraine, toothache, neuralgia, myalgia, algomenorrhea; pain in trauma, burns). Fever in infectious and inflammatory diseases.

Codral Tension Headache dosage and administration

Oral or rectally adults and adolescents with a body weight over 60 kg is used in a single dose of 500 mg, the multiplicity of admission - up to 4 times / Maximum duration of treatment - 5-7 days.

Maximum dose: single - 1 g, daily - 4 g.

Single dose for oral administration for children aged 6-12 years - 250-500 mg, 1-5 years - 120-250 mg, from 3 months to 1 year - 60-120 mg, up to 3 months - 10 mg / kg. Single dose rectal in children aged 6-12 years - 250-500 mg, 1-5 years - 125-250 mg.

Multiplicity - 4 at intervals of not less than 4 h. The maximum duration of treatment - 3 days.

Maximum dose: 4 single dose per day.

Codral Tension Headache side effects, adverse reactions

Digestive system: rarely - dyspepsia; long-term use at high doses - hepatotoxic effects, methemoglobinemia, renal dysfunction and liver, hypochromic anemia. Hemopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis. Allergic reactions: rarely - skin rash, itching, hives.

Contraindications

Chronic active alcoholism, increased sensitivity to Codral Tension Headache, marked disturbances of liver function and / or kidney disease, anemia, pregnancy (I term).

Using during pregnancy and breastfeeding

Codral Tension Headache (Acetaminophen) crosses the placental barrier. So far, no observed adverse effects of Codral Tension Headache (Acetaminophen) on the fetus in humans.

Codral Tension Headache (Acetaminophen) is excreted in breast milk: the content in milk was 0.04-0.23% of the dose adopted mother.

If necessary, use of Codral Tension Headache (Acetaminophen) during pregnancy and lactation (breastfeeding) should carefully weigh the potential benefits of therapy for the mother and the potential risk to the fetus or child.

In experimental studies found no embryotoxic, teratogenic and mutagenic action of Codral Tension Headache (Acetaminophen).

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Special Instructions

Codral Tension Headache is used with caution in patients with disorders of the liver and kidneys, with benign hyperbilirubinemia, as well as in elderly patients.

With prolonged use of Codral Tension Headache (Acetaminophen) is necessary to monitor patterns of peripheral blood and functional state of the liver.

Used for treatment of premenstrual tension syndrome in combination with pamabrom (diuretic, a derivative of xanthine) and mepyramine (Histamine H1-receptors blocker).

Codral Tension Headache (Acetaminophen) Drug Interactions

With the simultaneous use with inducers of microsomal liver enzymes, means having hepatotoxic effect, increasing the risk of hepatotoxic action of Codral Tension Headache (Acetaminophen).

With the simultaneous use of anticoagulants may be slight to moderate increase in prothrombin time.

With the simultaneous use of anticholinergics may decrease absorption of Codral Tension Headache (Acetaminophen).

With the simultaneous use of oral contraceptives accelerated excretion of Codral Tension Headache (Acetaminophen) from the body and may reduce its analgesic action.

With the simultaneous use with urological means reduced their effectiveness.

With the simultaneous use of activated charcoal reduced bioavailability of Codral Tension Headache (Acetaminophen).

When Codral Tension Headache (Acetaminophen) applied simultaneously with diazepam may decrease excretion of diazepam.

There have been reports about the possibility of enhancing mielodepression effect of zidovudine while applying with Codral Tension Headache (Acetaminophen). A case of severe toxic liver injury.

Described cases of toxic effects of Codral Tension Headache (Acetaminophen), while the use of isoniazid.

When applied simultaneously with carbamazepine, phenytoin, phenobarbital, primidonom decreases the effectiveness of Codral Tension Headache (Acetaminophen), which is caused by an increase in its metabolism and excretion from the body. Cases of hepatotoxicity, while the use of Codral Tension Headache (Acetaminophen) and phenobarbital.

In applying cholestyramine a period of less than 1 h after administration of Codral Tension Headache (Acetaminophen) may decrease of its absorption.

At simultaneous application with lamotrigine moderately increased excretion of lamotrigine from the body.

With the simultaneous use of metoclopramide may increase absorption of Codral Tension Headache (Acetaminophen) and its increased concentration in blood plasma.

When applied simultaneously with probenecid may decrease clearance of Codral Tension Headache (Acetaminophen), with rifampicin, sulfinpyrazone - may increase clearance of Codral Tension Headache (Acetaminophen) due to increasing its metabolism in the liver.

At simultaneous application of Codral Tension Headache (Acetaminophen) with ethinylestradiol increases absorption of Codral Tension Headache (Acetaminophen) from the gut.

Enhances the effect of indirect anticoagulants (coumarin derivatives and indandione). Antipyretic and analgesic activity of caffeine increases, reduce - rifampicin, phenobarbital and alcohol (accelerated biotransformation, inducing microsomal liver enzymes).

Codral Tension Headache in case of emergency / overdose

At a reception in toxic doses (10-15 g in adults) may develop liver necrosis.

Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, extreme tiredness, unusual bleeding or bruising, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms

Codeine Phosphate:


1 INDICATIONS AND USAGE

Codral Tension Headache (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 Codral Tension Headache (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.

Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and adjust the dosage accordingly .

2.2 Initial Dosage

Initiating Treatment with Codral Tension Headache Sulfate Tablets

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

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

2.3 Titration and Maintenance of Therapy

Individually titrate Codral Tension Headache (Codeine Phosphate) Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache Sulfate Tablets

When a patient who has been taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets regularly and may be physically dependent no longer requires therapy with Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient .

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3 DOSAGE FORMS AND STRENGTHS

Each 15 mg tablet for oral administration contains 15 mg of Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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

Codral Tension Headache (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 .

Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate). (4)
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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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Codral Tension Headache (Codeine Phosphate) Sulfate Tablets contain Codral Tension Headache (Codeine Phosphate), a Schedule II controlled substance. As an opioid, Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, and monitor all patients receiving Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are essential . Overestimating the Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of Codral Tension Headache (Codeine Phosphate).

5.3 Ultra-Rapid Metabolism of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate). Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate). Furthermore, children with obstructive sleep apnea who are treated with Codral Tension Headache (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:

  • Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
  • Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate). Breastfeeding is not recommended during treatment with Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets.

5.4 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Codral Tension Headache 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 Codral Tension Headache (Codeine Phosphate) are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codral Tension Headache (Codeine Phosphate) Sulfate Tablets requires careful consideration of the effects on the parent drug, Codral Tension Headache (Codeine Phosphate), and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Codral Tension Headache (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 Codral Tension Headache 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 Codral Tension Headache (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 Codral Tension Headache (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

Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and when Codral Tension Headache (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. Codral Tension Headache (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

Codral Tension Headache 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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets. In patients with circulatory shock, Codral Tension Headache (Codeine Phosphate) Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Codral Tension Headache (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), Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets.

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

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Codral Tension Headache Sulfate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The Codral Tension Headache (Codeine Phosphate) in Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) in Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in a physically-dependent patient, gradually taper the dosage . Do not abruptly discontinue Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in these patients .

5.15 Risks of Driving and Operating Machinery

Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and know how they will react to the medication .

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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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets.


Inhibitors of CYP3A4


Clinical Impact:


The concomitant use of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets with CYP3A4 inhibitors, may result in an increase in Codral Tension Headache (Codeine Phosphate) plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets is achieved .

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower Codral Tension Headache (Codeine Phosphate) levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Codral Tension Headache (Codeine Phosphate).


Intervention:


If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the Codral Tension Headache (Codeine Phosphate) Sulfate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.


Examples:


Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)


CYP3A4 Inducers


Clinical Impact:


The concomitant use of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and CYP3A4 inducers can result in lower Codral Tension Headache (Codeine Phosphate) levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions (5.5)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, Codral Tension Headache (Codeine Phosphate) plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.


Intervention:


If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Codral Tension Headache (Codeine Phosphate) Sulfate Tablets dosage as needed.

If a CYP3A4 inducer is discontinued, consider Codral Tension Headache (Codeine Phosphate) Sulfate Tablets dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals.


Examples:


Rifampin, carbamazepine, phenytoin


Inhibitors of CYP2D6


Clinical Impact:


Codral Tension Headache (Codeine Phosphate) is metabolized by CYP2D6 to form morphine. The concomitant use of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and CYP2D6 inhibitors can increase the plasma concentration of Codral Tension Headache (Codeine Phosphate), but can decrease the plasma concentration of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets is achieved .

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the Codral Tension Headache (Codeine Phosphate) plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression .


Intervention:


If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and monitor patients closely at frequent intervals.

If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Codral Tension Headache (Codeine Phosphate) Sulfate Tablets as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and monitor the patient for signs and symptoms of respiratory depression or sedation.


Examples


Paroxetine, fluoxetine, bupropion, quinidine.


Benzodiazepines and Other Central Nervous System (CNS) Depressants


Clinical Impact:


Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.


Intervention:


Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation .


Examples:


Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.


Serotonergic Drugs


Clinical Impact:


The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.


Intervention:


If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Codral Tension Headache (Codeine Phosphate) Sulfate Tablets if serotonin syndrome is suspected.


Examples:


Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).


Monoamine Oxidase Inhibitors (MAOIs)


Clinical Impact:


MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) .


Intervention:


Do not use Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in patients taking MAOIs or within 14 days of stopping such treatment.

If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.


Examples:


Phenelzine, tranylcypromine, linezolid.


Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics


Clinical Impact:


May reduce the analgesic effect of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and/or precipitate withdrawal symptoms.


Intervention:


Avoid concomitant use.


Examples:


Butorphanol, nalbuphine, pentazocine, buprenorphine.


Muscle Relaxants


Clinical Impact:


Codral Tension Headache (Codeine Phosphate) may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.


Intervention:


Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and/or the muscle relaxant as necessary.


Diuretics


Clinical Impact:


Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.


Intervention:


Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.


Anticholinergic Drugs


Clinical Impact:


The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.


Intervention:


Monitor patients for signs of urinary retention or reduced gastric motility when Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are used concomitantly with anticholinergic drugs.

  • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Codral Tension Headache (Codeine Phosphate) sulfate if serotonin syndrome is suspected. (7)
  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Codral Tension Headache (Codeine Phosphate) Sulfate Tablets because they may reduce analgesic effect of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, Codral Tension Headache (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. Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) during organogenesis.

Codral Tension Headache (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

Codral Tension Headache 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 Codral Tension Headache (Codeine Phosphate) via breast milk. Women who are ultra-rapid metabolizers of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) metabolism (normal CYP2D6 activity), the amount of Codral Tension Headache (Codeine Phosphate) secreted into human milk is low and dose-dependent.

There is no information on the effects of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets [see Warnings and Precautions (5.3)].

Clinical Considerations

If infants are exposed to Codral Tension Headache (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 Codral Tension Headache Sulfate Tablets in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate). Because of the risk of life-threatening respiratory depression and death:

  • Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are contraindicated for all children younger than 12 years of age .
  • Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression .

Codral Tension Headache (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 Codral Tension Headache in this patient population are unknown. Start these patients with a lower than normal dosage of Codral Tension Headache (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

Codral Tension Headache (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 Codral Tension Headache (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

Codral Tension Headache Sulfate Tablets contain Codral Tension Headache (Codeine Phosphate), a Schedule II controlled substance.

9.2 Abuse

Codral Tension Headache (Codeine Phosphate) Sulfate Tablets contains Codral Tension Headache (Codeine Phosphate), a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Codral Tension Headache (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.

Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets

Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are for oral use only. Abuse of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets poses a risk of overdose and death. The risk is increased with concurrent use of Codral Tension Headache (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.

Codral Tension Headache (Codeine Phosphate) Sulfate Tablets should not be abruptly discontinued in a physically-dependent patient . If Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of Codral Tension Headache (Codeine Phosphate) in Codral Tension Headache (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

Codral Tension Headache (Codeine Phosphate) Sulfate Tablets USP contain Codral Tension Headache (Codeine Phosphate), an opioid agonist, available for oral administration containing either 15 mg, 30 mg, or 60 mg of Codral Tension Headache (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:

Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets USP include: colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch and stearic acid.

chem.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Codral Tension Headache sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of Codral Tension Headache (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

Codral Tension Headache (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.

Codral Tension Headache (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

Codral Tension Headache (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

Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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

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

Food Effect: When 60 mg Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate).

Distribution

Codral Tension Headache (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. Codral Tension Headache (Codeine Phosphate) has low plasma protein binding with about 7% to 25% of Codral Tension Headache (Codeine Phosphate) bound to plasma proteins.

Elimination

Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) is excreted through the kidneys. The plasma half-lives of Codral Tension Headache (Codeine Phosphate) and its metabolites have been reported to be approximately 3 hours.

Metabolism: About 70% to 80% of the administered dose of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of Codral Tension Headache (Codeine Phosphate) to morphine and P450 3A4 is the major enzyme mediating conversion of Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) is excreted through the kidneys, of which approximately 10% is unchanged Codral Tension Headache (Codeine Phosphate). Plasma half-lives of Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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

Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) on male or female fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets with others and to take steps to protect Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) sulfate securely and to properly dispose of unused Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in accordance with the local state guidelines and/or regulations.

Ultra-Rapid Codral Tension Headache (Codeine Phosphate) Metabolism of Codral Tension Headache (Codeine Phosphate) and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Advise caregivers that Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets.

  • Advise patients not to adjust the dose of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets without consulting a physician or other healthcare professional.
  • If patients have been receiving treatment with Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (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 Codral Tension Headache (Codeine Phosphate) Sulfate Tablets

Advise patients to properly dispose of unused Codral Tension Headache (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


Codral Tension Headache (Codeine Phosphate) Sulfate (koe’ deen sul’ fate) Tablets USP CII


Codral Tension Headache (Codeine Phosphate) Sulfate Tablets are:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage mild to moderate pain, where treatment with an opioid is appropriate, and when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Codral Tension Headache (Codeine Phosphate) Sulfate Tablets:

  • Get emergency help right away if you take too much Codral Tension Headache (Codeine Phosphate) Sulfate Tablets (overdose). When you first start taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
  • Never give anyone else your Codral Tension Headache (Codeine Phosphate) Sulfate Tablets. They could die from taking it. Store Codral Tension Headache (Codeine Phosphate) Sulfate Tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away Codral Tension Headache (Codeine Phosphate) Sulfate Tablets is against the law.

Important Information Guiding Use in Pediatric Patients:

  • Do not give Codral Tension Headache (Codeine Phosphate) Sulfate Tablets to a child younger than 12 years of age.
  • Do not give Codral Tension Headache (Codeine Phosphate) Sulfate Tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.
  • Avoid giving Codral Tension Headache (Codeine Phosphate) Sulfate Tablets to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.

Do not take Codral Tension Headache (Codeine Phosphate) Sulfate Tablets if you have:

  • Severe asthma, trouble breathing, or other lung problems.
  • A bowel blockage or have narrowing of the stomach or intestines.
  • An allergy to Codral Tension Headache (Codeine Phosphate) Sulfate Tablets or any of the ingredients.

Before taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, tell your healthcare provider if you have a history of:

  • Head injury, seizures
  • Problems urinating
  • Abuse of street or prescription drugs, alcohol addiction, or mental health problems.
  • Liver, kidney, thyroid problems
  • Pancreas or gallbladder problems
  • Have been told by your healthcare provider that you are a “rapid metabolizer” of certain medicines

Tell your healthcare provider if you are:

  • Pregnant or planning to become pregnant. Prolonged use of Codral Tension Headache (Codeine Phosphate) sulfate during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • Breastfeeding. Not recommended; may harm your baby.
  • Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Codral Tension Headache (Codeine Phosphate) sulfate with certain other medicines can cause serious side effects that could lead to death.

When taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets:

  • Do not change your dose. Take Codral Tension Headache (Codeine Phosphate) Sulfate Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose every 4 hours as needed. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets regularly, do not stop taking Codral Tension Headache (Codeine Phosphate) sulfate without talking to your healthcare provider.
  • After you stop taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets, dispose the unused Codral Tension Headache (Codeine Phosphate) Sulfate Tablets in accordance with the local state guidelines and/or regulations.

While taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets DO NOT:

  • Drive or operate heavy machinery, until you know how Codral Tension Headache (Codeine Phosphate) sulfate affects you. Codral Tension Headache (Codeine Phosphate) sulfate can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Codral Tension Headache (Codeine Phosphate) sulfate may cause you to overdose and die.

The possible side effects of Codral Tension Headache (Codeine Phosphate) Sulfate Tablets:

  • Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

  • Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
  • If you are a nursing mother taking Codral Tension Headache (Codeine Phosphate) Sulfate Tablets and your breastfeeding baby has: increased sleepiness, confusion, difficulty breathing, shallow breathing, limpness, or difficulty breastfeeding.

These are not all the possible side effects of Codral Tension Headache (Codeine Phosphate) sulfate. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov


Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

For more information, please call West-Ward Pharmaceuticals at 1-800-962-8364.


This Medication Guide has been approved by the U.S. Food and Drug Administration


10005657/10

Revised August 2017

carton-15mg-tab-07.jpg

Doxylamine Succinate:


1 INDICATIONS AND USAGE

Codral Tension Headache (Doxylamine Succinate) is indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.

Limitations of Use

Codral Tension Headache (Doxylamine Succinate) has not been studied in women with hyperemesis gravidarum.

Codral Tension Headache (Doxylamine Succinate) is a fixed dose combination drug product of Codral Tension Headache (Doxylamine Succinate) succinate, an antihistamine, and pyridoxine hydrochloride, a Vitamin B6 analog, indicated for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management. (1)

2 DOSAGE AND ADMINISTRATION

Take two tablets daily at bedtime. If symptoms are not adequately controlled, the dose can be increased to a maximum recommended dose of four tablets daily as described in the full prescribing information. (2)

2.1 Dosage Information

Initially, take two Codral Tension Headache (Doxylamine Succinate) delayed-release tablets orally at bedtime (Day 1). If this dose adequately controls symptoms the next day, continue taking two tablets daily at bedtime. However, if symptoms persist into the afternoon of Day 2, take the usual dose of two tablets at bedtime that night then take three tablets starting on Day 3 (one tablet in the morning and two tablets at bedtime). If these three tablets adequately control symptoms on Day 4, continue taking three tablets daily. Otherwise take four tablets starting on Day 4 (one tablet in the morning, one tablet mid-afternoon and two tablets at bedtime).

The maximum recommended dose is four tablets (one in the morning, one in the mid-afternoon and two at bedtime) daily.

Take on an empty stomach with a glass of water . Swallow tablets whole. Do not crush, chew, or split Codral Tension Headache (Doxylamine Succinate) tablets.

Take as a daily prescription and not on an as needed basis. Reassess the woman for continued need for Codral Tension Headache (Doxylamine Succinate) as her pregnancy progresses.

3 DOSAGE FORMS AND STRENGTHS

Codral Tension Headache (Doxylamine Succinate) delayed-release tablets are white, round, film coated tablets containing 10 mg Codral Tension Headache (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. The tablets are imprinted with the pink image of a pregnant woman on one side.

Delayed-release tablets containing 10 mg Codral Tension Headache (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. (3)

4 CONTRAINDICATIONS

Codral Tension Headache (Doxylamine Succinate) is contraindicated in women with any of the following conditions:

  • Known hypersensitivity to Codral Tension Headache (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation
  • Monoamine oxidase (MAO) inhibitors intensify and prolong the adverse central nervous system effects of Codral Tension Headache (Doxylamine Succinate) .
  • Known hypersensitivity to Codral Tension Headache (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any inactive ingredient in the formulation (4)
  • Monoamine oxidase (MAO) inhibitors (4, 7)

5 WARNINGS AND PRECAUTIONS

  • Activities requiring mental alertness: Avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Codral Tension Headache until cleared to do so by a healthcare provider (5.1)
  • Central nervous system (CNS) depressants: Concurrent use with alcohol or other CNS depressants is not recommended (5.1)
  • Anticholinergic actions: Use with caution in patients with asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction (5.2)

5.1 Activities Requiring Mental Alertness

Codral Tension Headache (Doxylamine Succinate) may cause somnolence due to the anticholinergic properties of Codral Tension Headache (Doxylamine Succinate) succinate, an antihistamine. Women should avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Codral Tension Headache (Doxylamine Succinate) until cleared to do so by their healthcare provider.

Codral Tension Headache (Doxylamine Succinate) use is not recommended if a woman is concurrently using central nervous system (CNS) depressants including alcohol. The combination may result in severe drowsiness leading to falls or accidents .

5.2 Concomitant Medical Conditions

Codral Tension Headache (Doxylamine Succinate) has anticholinergic properties and, therefore, should be used with caution in women with: asthma, increased intraocular pressure, narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction and urinary bladder-neck obstruction.

6 ADVERSE REACTIONS

  • The following adverse reactions are discussed elsewhere in the labeling:
  • Somnolence
  • Falls or other accidents resulting from the effect of the combined use of Codral Tension Headache (Doxylamine Succinate) with CNS depressants including alcohol

The most common adverse reaction with Codral Tension Headache (Doxylamine Succinate) (≥5 percent and exceeding the rate in placebo) is somnolence. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay Inc. at 1-855-722-7734 or medicalinfoCodral Tension Headache (Doxylamine Succinate)duchesnayusa.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety and efficacy of Codral Tension Headache (Doxylamine Succinate) were compared to placebo in a double-blind, randomized, multi-center trial in 261 women with nausea and vomiting of pregnancy. The mean gestational age at enrollment was 9.3 weeks, range 7 to 14 weeks gestation . Adverse reactions for Codral Tension Headache (Doxylamine Succinate) that occurred at an incidence ≥5 percent and exceeded the incidence for placebo are summarized in Table 1.

Table 1: Number (Percent) of Subjects with ≥ 5 Percent Adverse Reactions in a 15‑Day Placebo-Controlled Study of Codral Tension Headache (Doxylamine Succinate) (Only Those Adverse Reactions Occurring at an Incidence ≥ 5 Percent and at a Higher Incidence with Codral Tension Headache (Doxylamine Succinate) than Placebo are Shown)


Codral Tension Headache (Doxylamine Succinate)

(N = 133)


Placebo

(n = 128)


Somnolence


19 (14.3%)


15 (11.7%)

6.2 Postmarketing Experience

The following adverse events, listed alphabetically, have been identified during post-approval use of the combination of 10 mg Codral Tension Headache (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride. Because these reactions are 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.

Cardiac disorders: dyspnea, palpitation, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: vision blurred, visual disturbances

Gastrointestinal disorders: abdominal distension, abdominal pain, constipation, diarrhea

General disorders and administration site conditions: chest discomfort, fatigue, irritability, malaise

Immune system disorders: hypersensitivity

Nervous system disorders: dizziness, headache, migraines, paresthesia, psychomotor hyperactivity

Psychiatric disorders: anxiety, disorientation, insomnia, nightmares

Renal and urinary disorders: dysuria, urinary retention

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash, rash maculo-papular

7 DRUG INTERACTIONS

  • Severe drowsiness can occur when used in combination with alcohol or other sedating medications.

7.1 Drug Interactions

Use of Codral Tension Headache (Doxylamine Succinate) is contraindicated in women who are taking monoamine oxidase inhibitors (MAOIs), which prolong and intensify the anticholinergic (drying) effects of antihistamines. Concurrent use of alcohol and other CNS depressants (such as hypnotic sedatives and tranquilizers) with Codral Tension Headache (Doxylamine Succinate) is not recommended.

7.2 Drug-Food Interactions

A food-effect study demonstrated that the delay in the onset of action of Codral Tension Headache (Doxylamine Succinate) may be further delayed, and a reduction in absorption may occur when tablets are taken with food . Therefore, Codral Tension Headache (Doxylamine Succinate) should be taken on an empty stomach with a glass of water [ see Dosage and Administration (2)].

8 USE IN SPECIFIC POPULATIONS

Pregnancy Category A. Codral Tension Headache is intended for use in pregnant women. (8.1)

8.1 Pregnancy

Pregnancy Category A

Codral Tension Headache (Doxylamine Succinate) is intended for use in pregnant women.

The combination of Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta-analyses) designed to detect possible teratogenicity. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no statistically significant relationships between fetal abnormalities and the first trimester use of the combination Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride.

Animal Data

The effects of Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride on embryofetal development have been studied in rats and monkeys.

Once daily treatment of pregnant rats with Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride during organogenesis (gestational day (GD) 6-15) resulted in increased fetal resorptions, decreased fetal body weight and increased skeletal variations with reduced ossification at doses 60 to 100 times the highest clinical dose based on body surface area.

Pregnant cynomolgus monkeys were treated once daily with Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride during organogenesis (GD 22-50). At birth, there were no observed malformations, and no evidence of embryo, fetal or maternal toxicity at doses up to 3.2 times the highest proposed clinical dose based on body surface area. In a similarly designed study in pregnant cynomolgus and rhesus monkeys and baboons, ventricular septal defects (VSDs) were observed in the preterm (GD 100) fetuses. Doses used in this study were 0.5-20 times higher than the clinical dose based on body surface area, with no relationship between dose and incidence of VSD. There were no VSDs in infant monkeys at term. No VSDs were observed at GD 100 in cynomolgus monkeys administered the combination of Codral Tension Headache (Doxylamine Succinate) succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.

8.3 Nursing Mothers

Women should not breastfeed while using Codral Tension Headache.

The molecular weight of Codral Tension Headache (Doxylamine Succinate) succinate is low enough that passage into breast milk can be expected. Excitement, irritability and sedation have been reported in nursing infants presumably exposed to Codral Tension Headache (Doxylamine Succinate) succinate through breast milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of Codral Tension Headache (Doxylamine Succinate) resulting in worsening of their apnea or respiratory conditions.

Pyridoxine hydrochloride is excreted into breast milk. There have been no reports of adverse events in infants presumably exposed to pyridoxine hydrochloride through breast milk.

8.4 Pediatric Use

The safety and effectiveness of Codral Tension Headache (Doxylamine Succinate) in children under 18 years of age have not been established.

Fatalities have been reported from Codral Tension Headache (Doxylamine Succinate) overdose in children. The overdose cases have been characterized by coma, grand mal seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3 year old child died 18 hours after ingesting 1,000 mg Codral Tension Headache (Doxylamine Succinate) succinate. However, there is no correlation between the amount of Codral Tension Headache (Doxylamine Succinate) ingested, the Codral Tension Headache (Doxylamine Succinate) plasma level and clinical symptomatology.

10 OVERDOSAGE

10.1 Signs and Symptoms of Overdose

Codral Tension Headache is a delayed-release formulation, therefore, signs and symptoms of intoxication may not be apparent immediately.

Signs and symptoms of overdose may include restlessness, dryness of mouth, dilated pupils, sleepiness, vertigo, mental confusion and tachycardia.

At toxic doses, Codral Tension Headache (Doxylamine Succinate) exhibits anticholinergic effects, including seizures, rhabdomyolysis, acute renal failure and death.

10.2 Management of Overdose

If treatment is needed, it consists of gastric lavage or activated charcoal, whole bowel irrigation and symptomatic treatment. For additional information about overdose treatment, call a poison control center (1‑800-222-1222).

11 DESCRIPTION

Codral Tension Headache (Doxylamine Succinate) (doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets are round, white, film-coated, delayed-release tablets containing 10 mg of Codral Tension Headache (Doxylamine Succinate) succinate and 10 mg of pyridoxine hydrochloride. Tablets are imprinted on one side with the pink image of a pregnant woman.

Inactive ingredients are as follows: ammonium hydroxide, n-butanol, carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, D&C Red#27, denatured alcohol, FD&C Blue#2, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer, microcrystalline cellulose 102, PEG 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Codral Tension Headache (Doxylamine Succinate) Succinate

Codral Tension Headache (Doxylamine Succinate) succinate is classified as an antihistamine. The chemical name for Codral Tension Headache (Doxylamine Succinate) succinate is ethanamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C17H22N2O - C4H6O4 and the molecular mass is 388.46. The structural formula is:

Codral Tension Headache (Doxylamine Succinate) succinate is a white to creamy white powder that is very soluble in water and alcohol, freely soluble in chloroform and very slightly soluble in ether and benzene.

Pyridoxine Hydrochloride

Pyridoxine hydrochloride is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride is 3,4-pyridinedimethanol, 5-hydroxy-6-methyl-, hydrochloride. The empirical formula is C8H11NO3 - HCl and the molecular mass is 205.64. The structural formula is:

Pyridoxine hydrochloride is a white or practically white crystalline powder that is freely soluble in water, slightly soluble in alcohol and insoluble in ether.

structure-1 structure-2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Codral Tension Headache is unknown.

12.3 Pharmacokinetics

The pharmacokinetics of Codral Tension Headache (Doxylamine Succinate) has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for Codral Tension Headache (Doxylamine Succinate) and pyridoxine, including its vitamin B6 metabolites, pyridoxal, pyridoxal 5’-phosphate, pyridoxamine and pyridoxamine 5’-phosphate, are summarized in Tables 2 to 5.

Absorption

A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of Codral Tension Headache (Doxylamine Succinate) administered in healthy non-pregnant adult women. Single-doses (two tablets at bedtime) were administered on Days 1 and 2. Multiple-doses (one tablet in the morning, one tablet in the afternoon and two tablets at bedtime) were administered on Days 3-18.

Blood samples for pharmacokinetic analysis were collected pre-and post-dose on Days 2 and 18 as well as pre-dose prior to bedtime dose only (trough) on Days 9, 10, 11, 16, 17, and 18.

Codral Tension Headache (Doxylamine Succinate) and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The Cmax of Codral Tension Headache (Doxylamine Succinate) and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.


Single Dose


Multiple Dose


AUC0-inf


Cmax


Tmax


AUC0-inf


Cmax


Tmax


(ng-h/mL)


(ng/mL)


(h)


(ng-h/mL)


(ng/mL)


(h)


Codral Tension Headache (Doxylamine Succinate)

1280.9 ± 369.3 83.3 ± 20.6 7.2 ± 1.9 3721.5 ± 1318.5 168.6 ± 38.5 7.8 ± 1.6

Pyridoxine

43.4 ± 16.5 32.6 ± 15.0 5.7 ± 1.5 64.5 ± 36.4 46.1 ± 28.3 5.6 ± 1.3

Pyridoxal

211.6 ± 46.1 74.3 ± 21.8 6.5 ± 1.4 1587.2 ± 550.0 210.0 ± 54.4 6.8 ± 1.2

Pyridoxal 5`Phosphate

1536.4 ± 721.5 30.0 ± 10.0 11.7 ± 5.3 6099.7 ± 1383.7 84.9 ± 16.9 6.3 ± 6.6

Pyridoxamine

4.1 ± 2.7 0.5 ± 0.7 5.9 ± 2.1 2.6 ± 0.8 0.5 ± 0.2 6.6 ± 1.4

Pyridoxamine 5'-phosphate

5.2 ± 3.8 0.7 ± 0.5 14.8 ± 6.6 94.5 ± 58.0 2.3 ± 1.7 12.4 ± 11.2

Multiple-dose administration of Codral Tension Headache (Doxylamine Succinate) results in increased concentrations of Codral Tension Headache (Doxylamine Succinate) as well as increases in Codral Tension Headache (Doxylamine Succinate) Cmax and AUC0-last of absorption. The time to reach the maximum concentration is not affected by multiple doses. The mean accumulation index is more than 1.0 suggesting that Codral Tension Headache (Doxylamine Succinate) accumulates following multiple dosing.

Although no accumulation was observed for pyridoxine, the mean accumulation index for each metabolite (pyridoxal, pyridoxal 5’-phosphate, and pyridoxamine 5’-phosphate) is more than 1.0 following multiple-dose administration of Codral Tension Headache (Doxylamine Succinate). The time to reach the maximum concentration is not affected by multiple doses.

AUC0-last (ng-h/mL) AUC0-inf (ng-h/mL) Cmax (ng/mL) Tmax (h) T1/2el (h)
Codral Tension Headache (Doxylamine Succinate)

Mean±SD

N=18


Single

911.4 ± 205.6 1280.9 ± 369.3 83.3 ± 20.6 7.2 ± 1.9 10.1 ± 2.1

Multiple

3661.3 ± 1279.2 3721.5 ± 1318.5 168.6 ± 38.5 7.8 ± 1.6 11.9 ± 3.3
Pyridoxine

Mean±SD

N=18


Single

39.3 ± 16.5 43.4 ± 16.5 32.6 ± 15.0 5.7 ± 1.5 0.5 ± 0.2

Multiple

59.3 ± 33.9 64.5 ± 36.4 46.1 ± 28.3 5.6 ± 1.3 0.5 ± 0.1

Food Effect

The administration of food delays the absorption of both Codral Tension Headache (Doxylamine Succinate) and pyridoxine. This delay is associated with a lower peak concentration of Codral Tension Headache (Doxylamine Succinate), but the extent of absorption is not affected.

The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxal, pyridoxamine, pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate metabolites also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its Cmax by 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5’-phosphate Cmax and extent of absorption. As for pyridoxamine and pyridoxamine 5’-phosphate, the rate and extent of absorption seem to decrease under fed conditions.

AUC0-t (ng-h/mL) AUC0-inf (ng-h/mL) Cmax (ng/mL) Tmax (h) T1/2el (h)
Codral Tension Headache (Doxylamine Succinate)

Mean±SD

N=42

Fasted 1407.2 ± 336.9 1447.9 ± 332.2 94.9 ± 18.4 5.1 ± 3.4 12.6 ± 3.4
Fed 1488.0 ± 463.2 1579.0 ± 422.7 N=37 75.7 ± 16.6 14.9 ± 7.4 12.5 ± 2.9
Pyridoxine

Mean±SD

N=42

Fasted 33.8 ± 13.7 39.5 ± 12.9 N=31 35.5 ± 21.4 2.5 ± 0.9 0.4 ± 0.2
Fed 18.3 ± 14.5 24.2 ±14.0 N=18 13.7 ± 10.8 9.3 ± 4.0 0.5 ± 0.2

Distribution

Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5’-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations.

Metabolism

Codral Tension Headache (Doxylamine Succinate) is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.

Pyridoxine is a prodrug primarily metabolized in the liver.

Excretion

The principle metabolites of Codral Tension Headache (Doxylamine Succinate), N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

The terminal elimination half-life of Codral Tension Headache (Doxylamine Succinate) and pyridoxine are 12.5 hours and 0.5 hours, respectively.

Table 5 – Terminal Elimination Half-Life (T1/2el) for Codral Tension Headache (Doxylamine Succinate) Administered as a Single Dose of Two Tablets under Fasting Conditions in Healthy Non-Pregnant Adult Women

T1/2el (h)
Doxylamine 12.6 ± 3.4
Pyridoxine 0.4 ± 0.2
Pyridoxal 2.1 ± 2.2
Pyridoxal 5’-Phosphate 81.6 ± 42.2
Pyridoxamine 3.1 ± 2.5
Pyridoxamine 5’-Phosphate

66.5 ± 51.3


Use in Specific Populations

Race: No pharmacokinetic studies have been conducted related to race.

Hepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.

Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Two-year carcinogenicity studies in rats and mice have been conducted with Codral Tension Headache (Doxylamine Succinate) succinate. Codral Tension Headache (Doxylamine Succinate) succinate is not likely to have human carcinogenic potential. The carcinogenic potential of pyridoxine hydrochloride has not been evaluated.

14 CLINICAL STUDIES

A double-blind, randomized, multi-center, placebo-controlled study was conducted to support the safety and efficacy of Codral Tension Headache (Doxylamine Succinate) in the treatment of nausea and vomiting of pregnancy. Adult women 18 years of age or older and 7 to 14 weeks gestation (median 9 weeks of gestation) with nausea and vomiting of pregnancy were randomized to 14 days of Codral Tension Headache (Doxylamine Succinate) or placebo. Two tablets of Codral Tension Headache (Doxylamine Succinate) were administered at bedtime on Day 1. If symptoms of nausea and vomiting persisted into the afternoon hours of Day 2, the woman was directed to take her usual dose of two tablets at bedtime that night and, beginning on Day 3, to take one tablet in the morning and two tablets at bedtime. Based upon assessment of remaining symptoms at her clinic visit on Day 4 (± 1 day), the woman may have been directed to take an additional tablet mid-afternoon. A maximum of four tablets (one in the morning, one in the mid-afternoon and two at bedtime) were taken daily.

Over the treatment period, 19% of DICLEGIS-treated patients remained on 2 tablets daily, 21% received 3 tablets daily, and 60% received 4 tablets daily.

The primary efficacy endpoint was the change from baseline at Day 15 in the Pregnancy Unique-Quantification of Emesis (PUQE) score. The PUQE score incorporates the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe).

At baseline, the mean PUQE score was 9.0 in the Codral Tension Headache (Doxylamine Succinate) arm and 8.8 in the placebo arm. There was a 0.7 (95% confidence interval 0.2 to 1.2 with p-value 0.006) mean decrease (improvement in nausea and vomiting symptoms) from baseline in PUQE score at Day 15 with Codral Tension Headache (Doxylamine Succinate) compared to placebo.

Table 6 – Change from Baseline in the Primary Endpoint, Pregnancy Unique-Quantification of Emesis (PUQE) Score at Day 15. (Intent-to-Treat Population with Last-Observation Carried Forward)

PUQE ScoreThe Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score incorporated the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe). Baseline was defined as the PUQE score completed at the enrollment visit. Codral Tension Headache (Doxylamine Succinate) Succinate + Pyridoxine Hydrochloride Placebo Treatment Difference [95% Confidence Interval]
Baseline

Change from baseline at Day 15

9.0 ± 2.1

-4.8 ± 2.7

8.8 ± 2.1

-3.9 ± 2.6

-0.7 [-1.2, -0.2]

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How supplied

Codral Tension Headache delayed-release tablets are supplied in a high-density polyethylene bottle with a polypropylene child-resistant cap and a silica gel desiccant canister. Each white, round, film-coated, delayed-release tablet contains 10 mg Codral Tension Headache (Doxylamine Succinate) succinate and 10 mg pyridoxine hydrochloride, and is imprinted on one side with the pink image of a pregnant woman. Codral Tension Headache (Doxylamine Succinate) tablets are provided as follows:

NDC 55494-100-10 Bottles of 100.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling

17.1 Somnolence and Severe Drowsiness

Inform women to avoid engaging in activities requiring complete mental alertness, such as driving or operating heavy machinery, while using Codral Tension Headache (Doxylamine Succinate) until cleared to do so.

Inform women of the importance of not taking Codral Tension Headache (Doxylamine Succinate) with alcohol or sedating medications, including other antihistamines (present in some cough and cold medications), opiates and sleep aids because somnolence could worsen leading to falls or other accidents.

Codral Tension Headache (Doxylamine Succinate)® is a registered trademark of Duchesnay Inc.

U.S. Patent Nos. 6,340,695 & 7,560,122.

Distributed by:

Duchesnay USA, Inc.

Bryn Mawr, PA, 19010

Tel: 1-855-722-7734

Fax: 1-888-588-8508

www.duchesnayusa.com

©2013, Duchesnay Inc. All rights reserved.

Patient Package Insert

Patient Information

Codral Tension Headache (Doxylamine Succinate) (dye-CLEE-gis)

(doxylamine succinate and pyridoxine hydrochloride) delayed-release tablets

What is Codral Tension Headache (Doxylamine Succinate)?

- Codral Tension Headache (Doxylamine Succinate) is a prescription medicine used to treat nausea and vomiting of pregnancy in

women who have not improved with change in diet or other non-medicine treatments.

- It is not known if Codral Tension Headache (Doxylamine Succinate) is safe and effective in children under 18 years of age.

Who should not take Codral Tension Headache (Doxylamine Succinate)?

Do not take Codral Tension Headache (Doxylamine Succinate) if you:

- are allergic to Codral Tension Headache (Doxylamine Succinate) succinate, other ethanolamine derivative antihistamines, pyridoxine hydrochloride or any of the ingredients in Codral Tension Headache (Doxylamine Succinate). See the end of this leaflet for a complete list of ingredients in Codral Tension Headache (Doxylamine Succinate).

- take monoamine oxidase inhibitors (MAOIs) (Marplan, Nardil, Emsam, Eldepryl, Zelapar, Parnate)

Before taking Codral Tension Headache (Doxylamine Succinate), tell your healthcare provider about all of your medical conditions, including;

- if you are breastfeeding or plan to breastfeed. Codral Tension Headache (Doxylamine Succinate) can pass into your breast milk and may harm your baby. You should not breastfeed while using Codral Tension Headache (Doxylamine Succinate).

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements.

How should I take Codral Tension Headache (Doxylamine Succinate)?

- Talk to your healthcare provider about how much Codral Tension Headache (Doxylamine Succinate) to take and when to take it.

- Take Codral Tension Headache (Doxylamine Succinate) everyday as prescribed by your healthcare provider. Do not stop taking Codral Tension Headache (Doxylamine Succinate) without talking to your healthcare provider first.

- See the following schedule for the usual way you should start taking Codral Tension Headache (Doxylamine Succinate):

- Day 1- Take 2 tablets, by mouth at bedtime.

- Day 2- Take 2 tablets at bedtime. If your nausea and vomiting is better or controlled on Day 2, continue to take 2 tablets every night at bedtime. This will be your usual dose unless your healthcare provider tells you otherwise.

- Day 3- If you still had nausea and vomiting on Day 2, take 3 tablets on Day 3 (1 tablet in the morning and 2 tablets at bedtime).

- Day 4- If your nausea and vomiting was better or controlled on Day 3, continue to take 3 tablets each day (1 tablet in the morning and 2 tablets at bedtime). If you still had nausea and vomiting on Day 3, start taking 4 tablets each day (1 tablet in the morning, 1 tablet in the afternoon, and 2 tablets at bedtime).

- Do not take more than 4 tablets (1 in the morning, 1 in the mid-afternoon, and 2 at bedtime) in 1 day.

- Take Codral Tension Headache (Doxylamine Succinate) on an empty stomach with a glass of water.

- Take Codral Tension Headache (Doxylamine Succinate) tablets whole. Do not crush, chew, or break Codral Tension Headache (Doxylamine Succinate) tablets before swallowing. If you cannot swallow Codral Tension Headache (Doxylamine Succinate) tablets whole, tell your healthcare provider.

- If you take too much Codral Tension Headache (Doxylamine Succinate) (overdose), you may have the following symptoms: restlessness, dry mouth, the pupils of your eyes become larger (dilated), sleepiness, dizziness, confusion, fast heart rate, seizures, muscle pain or weakness, and sudden and severe kidney problems. If you have these symptoms and they are severe, they may lead to death. Stop taking Codral Tension Headache (Doxylamine Succinate), call your healthcare provider or go to the nearest hospital emergency room right away. For more information about overdose treatment, call your poison control center at 1-800-222-1222.

What are the possible side effects of Codral Tension Headache (Doxylamine Succinate)?

Codral Tension Headache (Doxylamine Succinate) may cause serious side effects, including drowsiness.

- Do not drive, operate heavy machinery, or other activities that need your full attention unless your healthcare provider says that you may do so.

- Do not drink alcohol, or take other central nervous system depressants such as cough and cold medicines, certain pain medicines, and medicines that help you sleep while you take Codral Tension Headache (Doxylamine Succinate). Severe drowsiness can happen or become worse causing falls or accidents.

These are not all the possible side effects of Codral Tension Headache (Doxylamine Succinate).

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Codral Tension Headache (Doxylamine Succinate)?

- Store Codral Tension Headache (Doxylamine Succinate) between 68°F to 77°F (20°C to 25°C).

- Keep Codral Tension Headache (Doxylamine Succinate) tablets dry, in a tightly closed container, and out of the light.

- Safely throw away medicine that is out of date or no longer needed.

Keep Codral Tension Headache (Doxylamine Succinate) and all medicines out of the reach of children.

General information about the safe and effective use of Codral Tension Headache (Doxylamine Succinate).

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Codral Tension Headache (Doxylamine Succinate) that is written for health professionals. Do not use Codral Tension Headache (Doxylamine Succinate) for a condition for which it was not prescribed. Do not give Codral Tension Headache (Doxylamine Succinate) to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in Codral Tension Headache (Doxylamine Succinate)?

Active ingredient: Codral Tension Headache (Doxylamine Succinate) succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6)

Inactive ingredients: ammonium hydroxide, n-butanol, carnauba wax powder, colloidal silicon dioxide, croscarmellose sodium, D&C Red#27, denatured alcohol, FD&C Blue #2, hypromellose, isopropyl alcohol, magnesium stearate, magnesium trisilicate, methacrylic acid copolymer, microcrystalline cellulose 102, PEG 8000, polysorbate 80, propylene glycol, shellac glaze, simethicone, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate.

Distributed by: Duchesnay USA, Inc., Bryn Mawr, PA, 19010,

www.duchesnayusa.com or call 1-855-722-7734.

This Patient Information has been approved by the U.S. Food and Drug Administration

Issued: 05/2013

Bottle Label-Outside Front Cover with Imprint Area for Lot & Expiry

Bottle Label – Inside Cover

Codral Tension Headache pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Codral Tension Headache available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Codral Tension Headache destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Codral Tension Headache Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Codral Tension Headache pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."NINJACOF-XG (CODEINE PHOSPHATE) LIQUID [CENTURION LABS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."SAMBROSA SWEET DREAMS NIGHTTIME (DOXYLAMINE SUCCINATE) SYRUP [SAMBROSA CARE INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."FEVERALL INFANTS (ACETAMINOPHEN) SUPPOSITORY [ACTAVIS MID ATLANTIC LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Codral Tension Headache?

Depending on the reaction of the Codral Tension Headache after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Codral Tension Headache not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Codral Tension Headache addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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sdrugs.com conducted a study on Codral Tension Headache, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Codral Tension Headache consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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