Acetaminophen Caffeine Dihydrocodeine

Name: Acetaminophen Caffeine Dihydrocodeine

Acetaminophen Caffeine Dihydrocodeine Description

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Tablets are supplied in tablets form for oral administration.
Each tablet contains:
Acetaminophen .................... 325 mg
Caffeine ................................ 30 mg
Dihydrocodeine bitartrate ........ 16 mg

Acetaminophen (4'-hydroxyacetanilide), a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

C 8H 9NO 2
MW= 151.16

Caffeine (1,3,7-trimethylxanthine), a bitter, white crystalline powder or white glistening needles, is a central nervous system stimulant. It has the following structural formula:

C 8H 10N 4O 2
MW= 194.19

Dihydrocodeine Bitartrate (4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol (+)-tartrate), an odorless, fine white powder is an opioid analgesic. It has the following structural formula:

C 18H 23NO 3 • C 4H 6O 6
MW= 451.47

In addition, each tablet also contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid.

Indications and Usage for Acetaminophen Caffeine Dihydrocodeine

Acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are indicated for the relief of moderate to moderately severe pain.

Precautions

General:

Selection of patients for treatment with Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Tablets should be governed by the same principles that apply to the use of similar opioid/non-opioid fixed combination analgesics. As with any such opioid analgesic, the dosing regimen should be adjusted for each patient [see Dosage and Administration]. This combination product should be used with caution in elderly or debilitated patients or those with any of the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); asthma; central nervous system depression or coma; chronic obstructive pulmonary disease; decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis); delirium tremens; head injury; hypotension; increased intracranial pressure; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis. The benefits and risks of using opioids in patients taking monoamine oxidase inhibitors and in those with a history of drug abuse should be carefully considered. The administration of an analgesic containing an opioid may obscure the diagnosis or clinical course in patients with acute abdominal conditions. This combination product may aggravate convulsions in patients with convulsive disorders and, like all opioids, may induce or aggravate seizures in some clinical settings.

Acetaminophen is relatively non-toxic at therapeutic doses, but should be used with caution in patients with severe renal or hepatic disease. Care should be observed when using large doses of acetaminophen in malnourished patients or those with a history of chronic alcohol abuse because they may be more susceptible to hepatic damage similar to that observed with toxic overdosage. Caffeine in high doses may produce central nervous system and cardiovascular stimulation and gastrointestinal irritation.

Drug Interactions:

Dihydrocodeine with Other Central Nervous System Depressants:
Patients receiving other opioid analgesics, sedatives or hypnotics, muscle relaxants, general anesthetics, centrally acting anti-emetics, phenothiazines or other tranquilizers, or alcohol concomitantly with this combination product may exhibit additive depressant effects on the central nervous system. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Dihydrocodeine with Monoamine Oxidase Inhibitors:
Dihydrocodeine, like all opioid analgesics, interacts with monoamine oxidase inhibitors causing central nervous system excitation and hypertension.

Dihydrocodeine with Mixed Agonist/Antagonist Opioid Analgesics:
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) may reduce the analgesic effect of this combination product.

Acetaminophen Drug Interactions:
Chronic and excessive consumption of alcohol may increase the hepatotoxic risk of acetaminophen. The potential for hepatotoxicity with acetaminophen also may be increased in patients receiving anticonvulsants that induce hepatic microsomal enzymes (including phenytoin, barbiturates, and carbamazepine) or isoniazide. Chronic ingestion of large doses of acetaminophen may slightly potentiate the effects of warfarin and indandione- derivative anticoagulants. Severe hypothermia is possible in patients receiving acetaminophen concomitantly with phenothiazines.

Caffeine Drug Interactions:
Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Co-administration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Caffeine may increase the metabolism of other drugs such as phenobarbital and aspirin. Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin.

Information for Patients/Caregivers:

Patients receiving acetaminophen, caffeine and dihydrocodeine bitartrate tablets should be given the following information:

  1. Patients should be advised that acetaminophen, caffeine and dihydrocodeine bitartrate tablets may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
  2. Patients should be advised to report adverse experiences occurring during therapy.
  3. Patients should be advised not to adjust the dose of acetaminophen, caffeine and dihydrocodeine bitartrate tablets without consulting the prescribing professional.
  4. Patients should not combine acetaminophen, caffeine and dihydrocodeine bitartrate tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.
  5. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
  6. Patients should be advised that acetaminophen, caffeine, and dihydrocodeine bitartrate tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
  7. Do not take acetaminophen, caffeine, and dihydrocodeine bitartrate tablets if you are allergic to any of its ingredients.
  8. If you develop signs of allergy such as rash or difficulty breathing stop taking acetaminophen, caffeine, and dihydrocodeine bitartrate tablets and contact your healthcare provider immediately.
  9. Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Advise patients that some people have a genetic variation that results in dihydrocodeine changing into dihydromorphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid dihydrocodeine metabolizer or not. These higher-than-normal levels of dihydromorphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. Dihydrocodeine-containing products are contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving dihydrocodeine-containing products for other reasons to monitor for signs of respiratory depression.

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

Pregnancy:

Teratogenic Effects – Pregnancy Category C. Animal reproduction studies have not been conducted with acetaminophen, caffeine and dihydrocodeine bitartrate tablets. It is also not known whether this combination product can cause fetal harm when administered to pregnant women or can affect reproduction capacity in males and females. This combination product should be given to pregnant women only if clearly needed, especially during the first trimester.

Labor and Delivery:

Acetaminophen, caffeine and dihydrocodeine bitartrate tablets are not recommended for use by women during and immediately before labor and delivery because oral opioids may cause respiratory depression in the newborn.

Nursing Mothers:

Dihydrocodeine bitartrate is secreted into human milk. In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of dihydrocodeine. These women achieve higher-than-expected serum levels of dihydrocodeine’s active metabolite, dihydromorphine, leading to higher-than-expected levels of dihydromorphine in breast milk and potentially dangerously high serum dihydromorphine levels in their breastfed infants. Therefore, maternal use of dihydrocodeine can potentially lead to serious adverse reactions, including death, in nursing infants.

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

Dihydrocodeine bitartrate, acetaminophen and caffeine are also excreted in breast milk in small amounts. Because of the potential for serious adverse reactions in nursing infants from this combination product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Safety and effectiveness of acetaminophen, caffeine and dihydrocodeine bitartrate tablets in pediatric patients have not been established.

Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine.

Dihydrocodeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications].

Geriatric Use:

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Tablets should be given with caution to the elderly.

Hepatic Impairment:

Acetaminophen, caffeine and dihydrocodeine bitartrate tablets should be given with caution to patients with hepatic insufficiency. Since dihydrocodeine is metabolized by the liver and since acetaminophen potentially causes hepatotoxicity, the effects of this combination product should be monitored closely in such patients.

Renal Impairment:

Acetaminophen, caffeine and dihydrocodeine bitartrate tablets should be used with caution and at reduced dosage in the presence of impaired renal function.

Pancreatic/Biliary Tract Disease:

Opioids may cause spasms of the sphincter of Oddi and should be used with caution in patients with biliary tract disease including pancreatitis.

For the Consumer

Applies to acetaminophen / caffeine / dihydrocodeine: oral capsule, oral tablet

Along with its needed effects, acetaminophen / caffeine / dihydrocodeine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking acetaminophen / caffeine / dihydrocodeine:

More common
  • Abdominal or stomach pain or tenderness
  • bleeding gums
  • blood in the urine or stools
  • bloody, black, or tarry stools
  • chest pain
  • chills
  • clay colored stools
  • cough
  • dark urine
  • decreased appetite
  • dizziness
  • drowsiness
  • fever
  • headache
  • high fever
  • itching or skin rash
  • lightheadedness
  • loss of appetite
  • nausea and vomiting
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swelling of the feet or lower legs
  • swollen glands
  • unexplained or unusual bleeding or bruising
  • unusual tiredness or weakness
  • yellow eyes or skin
Rare
  • Agitation
  • coma
  • confusion
  • decreased urine output
  • difficulty with swallowing
  • fast heartbeat
  • hives
  • hostility
  • irritability
  • lethargy
  • muscle twitching
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • rapid weight gain
  • seeing, hearing, or feeling things that are not there
  • seizures
  • stupor
  • swelling of the face, ankles, or hands
  • tightness in the chest
Incidence not known
  • Cold sweats
  • darkening of the skin
  • decrease in the frequency of urination
  • decrease in the urine volume
  • difficult or troubled breathing
  • difficulty in passing urine (dribbling)
  • dizziness, faintness, or lightheadedness when getting up from lying or sitting position
  • fainting
  • irregular, fast or slow, or shallow breathing
  • overactive reflexes
  • pale or blue lips, fingernails, or skin
  • poor coordination
  • shivering
  • talking or acting with excitement you cannot control
  • trembling or shaking

Some side effects of acetaminophen / caffeine / dihydrocodeine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Difficulty having a bowel movement (stool)
  • drowsiness
  • relaxed and calm
  • sleepiness
Incidence not known
  • Constricted, pinpoint, or small pupils (black part of the eye)
  • diarrhea
  • dry mouth
  • gas in the stomach
  • heartburn
  • seeing, hearing, or feeling things that are not there

For Healthcare Professionals

Applies to acetaminophen / caffeine / dihydrocodeine: oral capsule, oral tablet

General

The most frequently expected adverse reactions based on the individual components may include lightheadedness, dizziness, drowsiness, sedation, nausea, vomiting, constipation, pruritus and skin reactions.[Ref]

Hepatic

Acetaminophen:
Frequency not reported: Hepatotoxicity[Ref]

Respiratory

Dihydrocodeine:
Frequency not reported: Respiratory depression, cough suppression[Ref]

Psychiatric

Dihydrocodeine:
Frequency not reported: Confusion, physical and psychological dependence, hallucinations vivid dreams

Caffeine:
Frequency not reported: Anxiety, anxiety neurosis, excitement, insomnia, irritability, restlessness, tenseness[Ref]

Dermatologic

Dihydrocodeine:
Frequency not reported: Sweating, pruritus, skin reactions

Acetaminophen:
Rare (less than 0.1%): Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

Caffeine:
Frequency not reported: Urticaria[Ref]

Hypersensitivity

Dihydrocodeine:
Frequency not reported: Anaphylactoid reactions, hypersensitivity reactions

Acetaminophen:
Rare (less than 0.1%): Anaphylactoid reactions
Frequency not reported: Hypersensitivity reactions including urticarial or erythematous skin reactions, laryngeal edema, angioedema[Ref]

Nervous system

Postmarketing reports: Serotonin syndrome

Dihydrocodeine:
Rare (less than 0.1%): Narcosis
Frequency not reported: Lightheadedness, dizziness, drowsiness, sedation, headache

Caffeine:
Frequency not reported: Headaches, lightheadedness, tremor[Ref]

Renal

Dihydrocodeine:
Rare (less than 0.1%): Acute renal failure
Frequency not reported: Granulomatous interstitial nephritis

Caffeine:
Frequency not reported: Diuresis[Ref]

Cardiovascular

Dihydrocodeine:
Frequency not reported: Orthostatic hypotension

Caffeine:
Frequency not reported: Extrasystoles, palpitations, tachycardia[Ref]

Endocrine

Postmarketing reports: Adrenal insufficiency

Opioids:
Frequency not reported: Androgen deficiency[Ref]

Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis and lead to androgen deficiency; however, the causal role of opioids is unknown due to the lack of studies into the many medical, physical, lifestyle, and psychological stressors that influence gonadal hormone levels.[Ref]

Gastrointestinal

Dihydrocodeine:
Frequency not reported: Nausea, vomiting, constipation, abdominal pain, diarrhea, dry mouth, indigestion, spasm of biliary tract

Caffeine:
Frequency not reported: Diarrhea, nausea, stomach pain, vomiting[Ref]

Genitourinary

Dihydrocodeine:
Frequency not reported: Urinary retention[Ref]

Hematologic

Acetaminophen:
Frequency not reported: Thrombocytopenia, leukopenia, pancytopenia, neutropenia, thrombocytopenic purpura, agranulocytosis[Ref]

Metabolic

Dihydrocodeine:
Frequency not reported: Anorexia[Ref]

Ocular

Dihydrocodeine:
Frequency not reported: Miosis

Caffeine:
Frequency not reported: Scintillating scotoma[Ref]

Other

Dihydrocodeine:
Frequency not reported: Fatigue

Caffeine:
Frequency not reported: Tinnitus[Ref]

Some side effects of acetaminophen / caffeine / dihydrocodeine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Liver Dose Adjustments

Use with caution; both acetaminophen and dihydrocodeine are metabolized by the liver; acetaminophen, especially at higher doses, may cause hepatotoxicity

Dose Adjustments

Dose adjustment may be required; however, no specific guidelines have been suggested; consider a lower dose in patients with renal impairment

Other Comments

Administration advice:
-Take orally; do not take more than 2 capsules in any 4-hour period

Storage requirements:
-Protect from light and moisture

General:
-Reserve use for patients who are unable to tolerate non-opioid analgesics and/or for those who non-opioid analgesics have not provided adequate analgesia.
-Acetaminophen induced hepatotoxicity is mostly preventable if maximum daily doses are not exceeded; patients should not use more than 1 acetaminophen-containing product at a time as this has been shown to increase the risk.
-Serious skin reaction may occur with acetaminophen use; discontinue at first appearance of skin rash or any other sign of hypersensitivity.

Monitoring:
-Monitor for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and after dose increases
-Monitor for signs of orthostatic hypotension, especially in those whose blood pressure is already compromised
-Monitor for signs of addiction, abuse or misuse
-Monitor for skin rash or other signs of hypersensitivity

Patient advice:
-Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
-Patients should understand the risks of life-threatening respiratory depression and when this risk is greatest. They should know that a genetic mutation may result in greater toxicity in some patients.
-Patients should be advised to check with their pharmacist or healthcare provider before starting or stopping any medications, including over the counter products and supplements.
-Patients should be instructed not to drive or operate heavy machinery until they know how this drug effects them.
-Patients should be advised not to drink alcohol or take other CNS depressants with this drug.
-Patients should be advised to store this drug safely out of the sight and reach of children; patients should be instructed in proper disposal.
-Women who are pregnant or are planning to become pregnant should discuss this with their healthcare provider.

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