Zanmbeel

Monday, May 17, 2010

Acetaminophen, caffeine, and dihydrocodeineAcetaminophen, caffeine, and dihydrocodeine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Panlor® DC 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.

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.

U.S. BRAND NAMES — Panlor® DC; Panlor® SS; Trezix®; ZerLor™

PHARMACOLOGIC CATEGORY
Analgesic Combination (Opioid)

DOSING: ADULTS — Relief of pain: Oral:

Panlor® DC, Trezix®: 2 capsules every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 10 capsules/24 hours)

Panlor® SS, ZerLor™ : 1 tablet every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 5 tablets/24 hours)

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule:
Panlor® DC: Acetaminophen 356.4 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg
Trezix®: Acetaminophen 356.4 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg

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

DOSAGE FORMS: CONCISE
Capsule:
Panlor® DC, Trezix®: Acetaminophen 356.4 mg, caffeine 30 mg, and dihydrocodeine 16 mg

Tablet:
Panlor® SS, ZerLor™ : Acetaminophen 712.8 mg, caffeine 60 mg, and dihydrocodeine 32 mg

GENERIC EQUIVALENT AVAILABLE — Yes: Tablet

USE — Relief of moderate to moderately-severe pain

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
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: Acetaminophen may cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Phenanthrene hypersensitivity: 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 total acetaminophen dose to <4 g/day.

RESTRICTIONS — 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
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. 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

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

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

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

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

Quinolone Antibiotics: May decrease the metabolism of Caffeine. Exceptions: Gatifloxacin; Gemifloxacin; Levofloxacin; Lomefloxacin; Moxifloxacin; Nalidixic Acid; Ofloxacin; Sparfloxacin; Trovafloxacin. 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

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 effect of Thiazide Diuretics. 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.

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 — (data from drugstore.com)
Capsules (Panlor DC)
356.4-30-16 mg (30): $46.99

Tablets (Panlor SS)
712.8-60-32 mg (30): $58.99

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

Acetaminophen, caffeine, and dihydrocodeineAcetaminophen, caffeine, and dihydrocodeine

Acetaminophen, aspirin, and caffeine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Excedrin® may be confused with Dexatrim®, Dexedrine®

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.

U.S. BRAND NAMES — Anacin® Advanced Headache Formula [OTC]; Excedrin® Extra Strength [OTC]; Excedrin® Migraine [OTC]; Fem-Prin® [OTC]; Genaced™ [OTC]; Goody's® Extra Strength Headache Powder [OTC]; Goody's® Extra Strength Pain Relief [OTC]; Pain-Off [OTC]; Vanquish® Extra Strength Pain Reliever [OTC]

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous

DOSING: ADULTS
Pain management:
Based on acetaminophen component:
Mild-to-moderate pain: Oral: 325-650 mg every 4-6 hours as needed; do not exceed 4 g/day
Mild-to-moderate pain associated with migraine headache: Oral: 500 mg/dose (in combination with 500 mg aspirin and 130 mg caffeine) every 6 hours while symptoms persist; do not use for longer than 48 hours
Based on aspirin component:
Mild-to-moderate pain: Oral: 325-650 mg every 4-6 hours as needed; do not exceed 4 g/day
Mild-to-moderate pain associated with migraine headache: Oral: 500 mg/dose (in combination with 500 mg acetaminophen and 130 mg caffeine) every 6 hours; do not use for longer than 48 hours

Product labeling:

Excedrin® Extra Strength, Excedrin® Migraine: Oral: 2 doses every 6 hours (maximum: 8 doses/24 hours)
Note: When used for migraine, do not use for longer than 48 hours

Goody's® Extra Strength Headache Powder: Oral: 1 powder, placed on tongue or dissolved in water, every 4-6 hours (maximum: 4 powders/24 hours)

Goody's® Extra Strength Pain Relief Tablets: Oral: 2 tablets every 4-6 hours (maximum: 8 tablets/24 hours)

Vanquish® Extra Strength Pain Reliever: Oral: 2 tablets every 4 hours (maximum: 12 tablets/24 hours)

DOSING: PEDIATRIC
Product labeling:

Excedrin® Extra Strength, Excedrin® Migraine: Oral: Children >12 years: Refer to adult dosing

Goody's® Extra Strength Headache Powder: Oral: Children >12 years: Refer to adult dosing

Goody's® Extra Strength Pain Relief Tablets: Oral: Children >12 years: Refer to adult dosing

Vanquish® Extra Strength Pain Reliever: Oral: Children >12 years: Refer to adult dosing

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:
Excedrin® Extra Strength, Excedrin® Migraine: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Vanquish® Extra Strength Pain Reliever: Acetaminophen 194 mg, aspirin 227 mg, and caffeine 33 mg

Geltab (Excedrin® Extra Strength, Excedrin® Migraine): Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Powder (Goody's® Extra Strength Headache Powder): Acetaminophen 260 mg, aspirin 520 mg, and caffeine 32.5 mg [contains lactose]

Tablet:
Anacin® Advanced Headache Formula: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Excedrin® Extra Strength, Excedrin® Migraine, Genaced™ , Pain-Off: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Fem-Prin®: Acetaminophen 194.4 mg, aspirin 226.8 mg, and caffeine 32.4 mg
Goody's® Extra Strength Pain Relief: Acetaminophen 130 mg, aspirin 260 mg, and caffeine 16.25 mg

DOSAGE FORMS: CONCISE
Caplet: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg; acetaminophen 194 mg, aspirin 227 mg, and caffeine 33 mg
Excedrin® Extra Strength [OTC], Excedrin® Migraine [OTC]: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Vanquish® Extra Strength Pain Reliever [OTC]: Acetaminophen 194 mg, aspirin 227 mg, and caffeine 33 mg

Geltab: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Excedrin® Extra Strength [OTC], Excedrin® Migraine [OTC]: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Powder: Acetaminophen 260 mg, aspirin 520 mg, and caffeine 32.5 mg
Goody's® Extra Strength Headache Powder [OTC]: Acetaminophen 260 mg, aspirin 520 mg, and caffeine 32.5 mg

Tablet:
Anacin® Advanced Headache Formula [OTC], Excedrin® Extra Strength [OTC], Excedrin® Migraine [OTC], Genaced™ [OTC], Pain-Off [OTC]: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg
Fem-Prin® [OTC]: Acetaminophen 194.4 mg, aspirin 226.8 mg, and caffeine 32.4 mg
Goody's® Extra Strength Pain Relief [OTC]: Acetaminophen 130 mg, aspirin 260 mg, and caffeine 16.25 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Relief of mild-to-moderate pain; mild-to-moderate pain associated with migraine headache

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, aspirin, salicylates, caffeine, or any component of the formulation; pregnancy

METABOLISM / TRANSPORT EFFECTS
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Aspirin: Substrate (minor) of CYP2C9

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

DRUG INTERACTIONS
ACE Inhibitors: Salicylates may diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy

Alendronate: Aspirin may enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy

Anticoagulants: Salicylates may enhance the anticoagulant effect of Anticoagulants. 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

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. 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

Calcium Channel Blockers (Nondihydropyridine): May enhance the anticoagulant effect of Salicylates. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. 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

Carbonic Anhydrase Inhibitors: Salicylates may enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Risk D: Consider therapy modification

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

Corticosteroids (Systemic): Salicylates may enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. 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

Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy

Drotrecogin Alfa: Salicylates may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Ginkgo Biloba: May enhance the antiplatelet effect of Salicylates. Risk D: Consider therapy modification

Heparin: Aspirin may enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk D: Consider therapy modification

Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

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

Ketorolac: May enhance the adverse/toxic effect of Aspirin. Risk X: Avoid combination

Loop Diuretics: Salicylates may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Risk C: Monitor therapy

Methotrexate: Salicylates may increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy

NSAID (Nonselective): May enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (Nonselective). Exceptions: Diclofenac. Risk D: Consider therapy modification

Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

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

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

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

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

Salicylates: May enhance the anticoagulant effect of other Salicylates. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Sulfonylureas: Salicylates may enhance the hypoglycemic effect of Sulfonylureas. Of concern with regular, higher doses of salicylates, not sporadic, low doses. Risk C: Monitor therapy

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

Thrombolytic Agents: Salicylates may enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

Tiludronate: Aspirin may decrease the serum concentration of Tiludronate. Risk C: Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk C: Monitor therapy

Uricosuric Agents: Salicylates may diminish the therapeutic effect of Uricosuric Agents. Specifically, uricosuria. Risk C: Monitor therapy

Valproic Acid: Salicylates may increase the serum concentration of Valproic Acid. Risk C: Monitor therapy

Varicella Virus-Containing Vaccines: Salicylates may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. Reye's Syndrome may develop. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Salicylates may enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

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 hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

PREGNANCY RISK FACTOR — D (show table)

PHARMACODYNAMICS / KINETICS — See individual agents.

Acetaminophen, aspirin, and caffeine

Acetaminophen and tramadol

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Ultracet® may be confused with Ultane®, Ultram®

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.

U.S. BRAND NAMES — Ultracet®

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous
Analgesic, Opioid

DOSING: ADULTS — Acute pain: Oral: Two tablets every 4-6 hours as needed for pain relief (maximum: 8 tablets/day); treatment should not exceed 5 days

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Clcr <30 mL/minute: Maximum of 2 tablets every 12 hours. Treatment should not exceed 5 days.

DOSING: HEPATIC IMPAIRMENT — Use is not recommended.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet: Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg
Ultracet®: Acetaminophen 325 mg and tramadol hydrochloride 37.5 mg

DOSAGE FORMS: CONCISE
Tablet: Acetaminophen 325 mg and tramadol 37.5 mg
Ultracet®: Acetaminophen 325 mg and tramadol 37.5 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Short-term (≤ 5 days) management of acute pain

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Somnolence (6%), dizziness (3%), insomnia (2%), anxiety, confusion, euphoria, fatigue, headache, nervousness, tremor
Dermatologic: Pruritus (2%), rash
Endocrine & metabolic: Hot flashes
Gastrointestinal: Constipation (6%), anorexia (3%), diarrhea (3%), nausea (3%), dry mouth (2%), abdominal pain, dyspepsia, flatulence, vomiting
Genitourinary: Prostatic disorder (2%)
Neuromuscular & skeletal: Weakness
Miscellaneous: Diaphoresis increased (4%)

<1% (Limited to important or life-threatening): Allergic reactions, amnesia, anaphylactoid reactions, anaphylaxis, arrhythmia, coma, depersonalization, drug abuse, dysphagia, dyspnea, emotional lability, hallucination, hepatitis, hypertonia, impotence, liver failure, migraine, muscle contractions (involuntary), oliguria, paresthesia, paroniria, pulmonary edema, rigors, seizure, serotonin syndrome, shivering, Stevens-Johnson syndrome, suicidal tendency, stupor, syncope, tinnitus, tongue edema, toxic epidermal necrolysis, urinary retention, urticaria, vertigo

A withdrawal syndrome may occur with abrupt discontinuation; includes anxiety, diarrhea, hallucinations (rare), nausea, pain, piloerection, rigors, sweating, and tremor. Uncommon discontinuation symptoms may include severe anxiety, panic attacks, or paresthesia.

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, tramadol, opioids, or any component of the formulation; opioid-dependent patients; acute intoxication with ethanol, hypnotics, narcotics, centrally-acting analgesics, opioids, or psychotropic drugs; hepatic dysfunction

WARNINGS / PRECAUTIONS
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: May cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Seizures: Even when taken within the recommended dosage seizures may occur; risk is increased in patients receiving serotonin reuptake inhibitors (SSRIs or anorectics), tricyclic antidepressants, other cyclic compounds (including cyclobenzaprine, promethazine), neuroleptics, MAO inhibitors, or drugs which may lower seizure threshold. Patients with a history of seizures, or with a risk of seizures (head trauma, metabolic disorders, CNS infection, malignancy, or during alcohol/drug withdrawal) are also at increased risk.

Disease-related concerns: Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. 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. Renal impairment: Use tramadol with caution and reduce dosage in patients with renal impairment. Respiratory disease: Patients with chronic respiratory disorders may be at greater risk of adverse events.

Concurrent drug therapy issues: CNS depressants: Use with caution and reduce dosage when administering to patients receiving other CNS depressants. MAO inhibitors: Should be used only with extreme caution in patients receiving 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. Decrease initial dose. Pediatrics: Safety and efficacy have not been established in children.

Other warnings/precautions: Dosage limit: Limit acetaminophen dose to <4 g/day. Withdrawal: Tolerance or drug dependence may result from extended use (withdrawal symptoms have been reported); abrupt discontinuation should be avoided. Tapering of dose at the time of discontinuation limits the risk of withdrawal symptoms.

METABOLISM / TRANSPORT EFFECTS
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Tramadol: Substrate of CYP2D6 (major), 3A4 (major)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). 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

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. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

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

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

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

MAO Inhibitors: TraMADol may enhance the neuroexcitatory and/or seizure-potentiating effect of MAO Inhibitors. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

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

Selective Serotonin Reuptake Inhibitors: May enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. TraMADol may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

Tricyclic Antidepressants: May enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. 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: Avoid ethanol (increased liver toxicity with concomitant use).

Food: May delay time to peak plasma levels, however, the extent of absorption is not affected.

Herb/Nutraceutical:
Acetaminophen: Avoid St John's wort (may decrease acetaminophen levels).
Tramadol: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Tramadol has been shown to cross the placenta. Postmarketing reports following tramadol use during pregnancy include neonatal seizures, withdrawal syndrome, fetal death, and stillbirth. Not recommended for use during labor and delivery.

LACTATION — Tramadol: Enters breast milk/contraindicated

BREAST-FEEDING CONSIDERATIONS — Not recommended for postdelivery analgesia in nursing mothers.

DIETARY CONSIDERATIONS — May be taken with or without food. Avoid use of ethanol and ethanol-containing products.

PRICING — (data from drugstore.com)
Tablets (Tramadol-Acetaminophen)
37.5-325 mg (30): $27.99

Tablets (Ultracet)
37.5-325 mg (30): $54.32

MONITORING PARAMETERS — Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance or abuse

CANADIAN BRAND NAMES — Tramacet

INTERNATIONAL BRAND NAMES — Calmex (PY); Dolcet (PH); Ixprim (FR); Tramacet (BB, BM, BS, BZ, DO, GB, GY, IE, JM, MX, NL, SR, TT); Ultracet (BR, HK, ID, KP, MY, SG, TH, TW, VE); Zaldiar (BE, CH, CN, CO, CR, CZ, DE, DO, EE, ES, FR, GT, HN, ID, IL, MX, NI, NL, PA, PE, SV, VE); Zultracet (PK)

MECHANISM OF ACTION
Based on acetaminophen component: 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

Based on tramadol component: Binds to µ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which also modifies the ascending pain pathway

PHARMACODYNAMICS / KINETICS — See individual agents.

Acetaminophen and tramadol

Acetaminophen and pseudoephedrine

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Ornex® may be confused with Orexin®, Orinase®

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.

SPECIAL ALERTS
Health Canada: Labeling Changes for OTC Cough and Cold Preparations - December, 2008

Health Canada has issued an advisory to Canadian consumers regarding upcoming labeling changes for the use of over-the-counter (OTC) cough and cold medicines in children. Specific labeling changes as well as other important information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2008/2008_184-eng.php.

Manufacturers Voluntarily Change Pediatric OTC Product Labeling - October 7, 2008

Leading manufacturers of over-the-counter (OTC) pediatric cough and cold products, in consultation with the Food and Drug Administration (FDA), have announced that they are voluntarily transitioning product labeling as it relates to children <4 years of age. The decision to change the labeling followed a meeting on October 2, 2008, conducted by the FDA to gather additional information related to the use of these products in children. The safety of the ingredients in these products was not in question. It was found that dosing errors and accidental ingestions were the leading cause of rare adverse events in children. The new product labeling will state "Do not use in children under four years of age." In addition, products with certain antihistamines will warn parents not to use these products to sedate or make a child sleepy. Labeling of adult products will not change. New product labels will be introduced during the 2008-2009 cough and cold season and some products will have the updated labeling by mid-October. Products with the old labeling will not be removed from the market. Prescription products are not affected.

It is important to note that these medications have not been shown to be unsafe when used correctly. Pharmacists may continue to see health care practitioners recommending these agents for use in pediatric patients, and should help to ensure that they are being used safely and at appropriate dosages. Parents should be advised that OTC cough and cold products are safe and effective when used as directed, but that they should not be used in children <4 years of age unless instructed to do so by their healthcare provider. Counseling tips from the Consumer Healthcare Products Association (CHPA) also include: Always follow dosing instructions exactly and use measuring devices provided with the medicine. Never give 2 medicines at the same time that contain the same active ingredient. Do not give a medicine intended for use in adults to a child.

Additional tips and information related to the labeling changes can be found on the following educational website of the CHPA: http://www.otcsafety.org.

The FDA had previously issued a Public Health Advisory reminding patients and caregivers that OTC cough and cold medications should not be used to treat infants and children <2 years of age. This is in response to the Centers for Disease Control and Prevention (CDC) report which noted that during 2004 and 2005, ~1519 children <2 years of age were seen in emergency departments for adverse effects, including overdose, associated with products containing nasal decongestants (eg, pseudoephedrine), antihistamines (eg, carbinoxamine), and cough suppressants (eg, dextromethorphan). In October of 2007, several manufacturers voluntarily removed these products in order to help reduce dosing errors and overdose in this age group.

For additional information, refer to the following websites:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm094913.htm

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116839.htm

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5601a1.htm, Centers for Disease Control, "Infant Deaths Associated with Cough and Cold Medications - Two States, 2005,"MMWR Morb Mortal Wkly Rep, 2007, 56(01):1-4.

U.S. BRAND NAMES — Ornex® Maximum Strength [OTC]; Ornex® [OTC]

PHARMACOLOGIC CATEGORY
Alpha/Beta Agonist
Analgesic, Miscellaneous

DOSING: ADULTS — Relief of cold, flu or sinusitis symptoms: Oral (Ornex®, Ornex® Maximum Strength): Two caplets every 4-6 hours as needed (maximum: 8 caplets/day)

DOSING: PEDIATRIC
Relief of cold, flu or sinusitis symptoms: Oral:

Children 6-11 years (Ornex®): One caplet every 4-6 hours as needed (maximum: 4 caplets/day)

Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis; however, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:
Ornex®: Acetaminophen 325 mg and pseudoephedrine hydrochloride 30 mg
Ornex® Maximum Strength: Acetaminophen 500 mg and pseudoephedrine hydrochloride 30 mg

DOSAGE FORMS: CONCISE
Caplet:
Ornex®: Acetaminophen 325 mg and pseudoephedrine 30 mg
Ornex® Maximum Strength: Acetaminophen 500 mg and pseudoephedrine 30 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Temporary relief of nasal congestion, and minor aches and pains associated with colds, flu, sinusitis, or allergies

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — MAO inhibitor therapy or within 14 days of therapy; concurrent use with other products containing acetaminophen

WARNINGS / PRECAUTIONS
Disease-related concerns: Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥ 3 alcoholic drinks/day may increase the risk of liver damage. Hepatic impairment: Use caution in patients with hepatic impairment; acetaminophen may cause severe hepatic toxicity with acute overdose.

Special populations: Pediatrics: Do not exceed pediatric dosing recommendations. If no recommendations exist on OTC labeling for patient's age, the product should not be administered without the guidance of a physician.

Other warnings/precautions: Dosage limit: Limit acetaminophen dose to <4>7 days or are accompanied by fever that lasts for >3 days, consult a physician. Discontinue and contact healthcare provider if nervousness, dizziness, or sleeplessness occur.

METABOLISM / TRANSPORT EFFECTS — Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Antacids: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Aluminum Hydroxide. 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

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

Bromocriptine: Alpha-/Beta-Agonists may enhance the adverse/toxic effect of Bromocriptine. Including increased blood pressure, ventricular arrhythmias, and seizure. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. 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

Carbonic Anhydrase Inhibitors: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Brinzolamide; Dorzolamide. 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

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

MAO Inhibitors: May enhance the hypertensive effect of Alpha-/Beta-Agonists (Indirect-Acting). Risk X: Avoid combination

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

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification

Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. 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 hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

CANADIAN BRAND NAMES — Contac® Cold and Sore Throat, Non Drowsy, Extra Strength; Dristan® N.D.; Dristan® N.D., Extra Strength; Sinutab® Non Drowsy; Sudafed® Head Cold and Sinus Extra Strength; Tylenol® Decongestant; Tylenol® Sinus

INTERNATIONAL BRAND NAMES — Panadol Sinus (AU, HK); Sinumax Ped (ZA); Sinutab (BE)

PHARMACODYNAMICS / KINETICS — See individual agents.

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Monday, May 17, 2010