Acetaminophen, caffeine, and dihydrocodeine

Acetaminophen, caffeine, and dihydrocodeine: Drug information
Copyright 1978-2011 Lexicomp, Inc. All rights reserved.
(For additional information see “Acetaminophen, caffeine, and dihydrocodeine: Patient drug information”)

Special Alerts
Acetaminophen: Change in Maximum Content of Prescription Products and Labeling Changes January 2011
The Food and Drug Administration (FDA) is asking manufacturers to limit the strength of acetaminophen in prescription products to 325 mg per dosage unit. Drug manufacturers will have until January 14, 2014 to comply with the FDA’s request. The dosing instructions of prescription acetaminophen products will not change. For example, the instructions of 1-2 tablets every 4-6 hours for a combination product of acetaminophen 500 mg with an opioid can still be used for a combination product of acetaminophen 325 mg with an opioid.

The FDA is also notifying healthcare professionals of labeling changes for all prescription products that contain acetaminophen. A Boxed Warning will be required on all prescription acetaminophen products to describe the potential risk of severe liver injury. Additionally, the FDA has asked manufacturers to add a Warning regarding the potential for allergic reactions, including anaphylaxis.

Healthcare professionals should advise patients:

– not to exceed 4 g/day of acetaminophen

– not to take multiple acetaminophen-containing products (including over-the-counter products)

– not to consume alcohol while taking acetaminophen-containing products

– that severe liver injury and cases of hypersensitivity reactions (including anaphylaxis) have occurred with the use of acetaminophen

– to report taking more acetaminophen than directed

– to report any adverse events that may have occurred with the use of acetaminophen

Further information may be found at: file://www.fda.gov/Drugs/DrugSafety/ucm239821.htm

ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Brand Names: U.S. Panlor® SS [DSC]; Trezix™; ZerLor™ [DSC]
Pharmacologic Category Analgesic Combination (Opioid)
Dosing: Adult Relief of pain: Oral:
Panlor® SS, ZerLor™: One tablet every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 5 tablets/24 hours)

Trezix™: Two capsules every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 10 capsules/24 hours)

Dosing: Geriatric Refer to adult dosing.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule:

Trezix™: Acetaminophen 356.4 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg

Tablet: Acetaminophen 712.8 mg, caffeine 60 mg, and dihydrocodeine bitartrate 32 mg

Panlor® SS [DSC], ZerLor™ [DSC]: Acetaminophen 712.8 mg, caffeine 60 mg, and dihydrocodeine bitartrate 32 mg

Generic Equivalent Available: U.S. Yes: Tablet
Use Relief of moderate to moderately-severe pain
Medication Safety Issues
Sound-alike/look-alike issues:
Panlor® may be confused with Pamelor®

High alert medication:
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

Adverse Reactions Significant Frequency not defined. Most common reactions with this combination include:
Central nervous system: Dizziness, drowsiness, lightheadedness, sedation

Dermatologic: Pruritus, skin reactions

Gastrointestinal: Constipation, nausea, vomiting

Contraindications Hypersensitivity to acetaminophen, caffeine, dihydrocodeine, codeine, or any component of the formulation; significant respiratory depression (in unmonitored settings); acute or severe bronchial asthma; hypercapnia; paralytic ileus
Warnings/Precautions
Boxed warnings:

• Hepatotoxicity: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hepatotoxicity: [U.S. Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Risk is increased with alcohol use, pre-existing liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur. Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

Disease-related concerns:

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison’s disease.

• CNS depression/coma: Use with caution in patients with CNS depression or coma.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Hypotension: Use with caution in patients with hypotension.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Renal impairment: Use with caution in patients with severe renal impairment.

• Respiratory disease: Use with caution in patients with respiratory diseases including asthma, emphysema, and/or COPD.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• MAO inhibitors: Use with caution with concurrent use of MAO inhibitors.

Special populations:

• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects.

• Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions:

• Caffeine: May cause CNS and cardiovascular stimulation, as well as GI irritation in high doses. Use with caution in patients with a history of peptic ulcer or GERD; avoid in patients with symptomatic cardiac arrhythmias.

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.

Controlled Substance C-III
Metabolism/Transport Effects
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Caffeine: Substrate of CYP1A2 (major), 2C9 (minor), 2D6 (minor), 2E1 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 3A4 (moderate)

Dihydrocodeine: Substrate of CYP2D6 (minor)

Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Adenosine: Caffeine may diminish the therapeutic effect of Adenosine. Risk D: Consider therapy modification

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Formoterol: Caffeine may enhance the adverse/toxic effect of Formoterol. Caffeine may enhance the hypokalemic effect of Formoterol. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

QuiNIDine: May diminish the analgesic effect of Dihydrocodeine. Risk D: Consider therapy modification

Quinolone Antibiotics: May decrease the metabolism of Caffeine. Exceptions: Gemifloxacin; Levofloxacin; Levofloxacin (Systemic); Lomefloxacin; Moxifloxacin; Moxifloxacin (Systemic); Nalidixic Acid; Ofloxacin; Ofloxacin (Systemic); Sparfloxacin. Risk C: Monitor therapy

Regadenoson: Caffeine may diminish the vasodilatory effect of Regadenoson. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced toxicity. Ethanol may also increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Pregnancy Risk Factor C (show table)
Pregnancy Implications Reproduction studies have not been conducted with this combination.
Lactation Enters breast milk/not recommended
Breast-Feeding Considerations Acetaminophen and caffeine are both excreted in breast milk. Specific information for dihydrocodeine is not available; however, similar agents (eg, codeine, morphine) are excreted in breast milk.
Pricing: U.S. (www.drugstore.com)
Tablets (APAP-Caff-Dihydrocodeine)

712.8-60-32 mg (100): $155.99

Tablets (Panlor SS)

712.8-60-32 mg (30): $56.99

Mechanism of Action
Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center.

Caffeine is a CNS stimulant; use with acetaminophen and dihydrocodeine increases the level of analgesia provided by each agent.

Dihydrocodeine binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.

 

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