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Patient Profile for: C.P. Rudhom

Personal Information

Date: 3-1-06

Patient ID: # 2-20060301CPP

Attending Physician: xxxxxxxxxxxxxMD

Patient Name: C. P. Rudhom

Address: xxxxxxxxxxxxxxxx

City: xxxxxxxxxx

State: LA

Zipcode: xxxxx

Country: USA

Phone: (xxx) xxx-xxxx

____________________________________________________________________________________

Medical Information

____________________________________________________________________________________

Diagnosis:

Diabetes mellitus S/P paraplegia Hypoalbuminemia

Depression Seizure disorder Organic Brain Syndrome

Bipolar Disorder Neurogenic bladder GERD

Insomnia, NOS Anxiety Hx of pneumonia

S/P CVA with left hemiplegia

General complaints not listed as diagnosis by your doctor:

No desire to participate in social activities, significant decrease in appetite, eats only when assisted but is capable of feeding self. Patient is frequently hostile and has inappropriate impulsive behaviors.

March 1, 2006

Physical & sexual aggression and inappropriate sexually oriented remarks

Complaints of pain to hips, shoulders, knees, fingers and back

Complaints of insomnia described as sleep onset and maintenance(Chronic)

Complaints of orhtopnea

Allergies: No known allergies reported.

Hamilton Rating Depression score = 29 significant clinical depression

Current Medications: Total 20 medicatons

Albuterol Inhalation solution 0.083% 3ml(2.5mg) per nebulizer treatment q 4 hrs while awake.

Seroquel 100mg tablets 1 tab po q day 6-8-05
Seroquel 200mg tablets 1 tab po hs 6-8-05
Seroquel 25mg tablet 1 po q day at 4pm 9-29-05
Tramadol 50mg tablets 1 tab po bid 6-8-05
Vitamin C 500mg tablets 1 tab po q day 6-8-05
Wellbutrin XL 300mg tablet 1 tab po q day 6-8-05
Avandia 4mg tablet 1 tab po q day 6-8-05
Furosemide 40mg tablet 1 tab po q day 6-8-05
Protonix 40mg tablet 1 tab po hs 6-8-05
Depakote 500mg capsule 1 cap po bid 6-8-05
Zinc sulfate 220mg tablet 1 tab po q day 6-8-05
Magnesium Oxide 440mg tablet 1 tab po bid 6-8-05
DHEA 50mg tablet 1 tab po bid 6-8-05
Glucophage 500mg tablet 1 tab po bid 7-5-05
KCL 20mEq tablet 1 tab po bid 7-1-05
Trazodone 100mg tablet 1 tab po hs 7-5-05
Miralax powder 1 capful po q day 7-21-05
Hydrocodone/APAP 10mg tablet 1 tab po qid 8-16-05
Restoril 30mg capsule 1 cap po hs 9-29-05
Depo-Testosterone 20mg/ml inj 75mg IM q week 9-29-05
Vitamin E 400IU capsules 1 cap po q day 12-30-05

Labs:

CBC of 2-06:

RBC 3.81 Hgb 11.8 Hct 36.6 MCV WNL RDW 17.8

CMP of 2-06:

BUN/Cr 44 Na 136 K+ 4.4

Cl 99 AkPhos55 CO2 33 Cr 0.6

Alb 2.6 Ca 8.5 corrected 9.62 Valproic acid 71

Testosterone 697 Glucose 69 SGOT 40 slightly elevated

Urinalysis none available

The following recommendations were made:

Albuterol Inhalation solution 0.083% 3ml(2.5mg) per nebulizer treatment q 4 hrs while awake.

Use of Albuterol may be causing many of his problems related to hostility, agitation, loss of appetite and insomnia.
Recommendation:
Use of a long acting bronchodilator could be tried to see if a once a day therapy is viable. Use of Spiriva Handihaler 17mcg inhaled each AM may provide the support with fewer problems. (mouth should be washed out well after each application) changed albuterol to prn only
Potential Savings: Albuterol cost $ 124.98 - Spiriva cost = $ 129.55 = -4.57
Actual Savings from change: Switched to PRN savings = $ 62.49

Seroquel 100mg tablets 1 tab po q day 6-8-05
Seroquel 200mg tablets 1 tab po hs 6-8-05
Seroquel 25mg tablet 1 po q day at 4pm 9-29-05

Seroquel therapy seems to be failing. Use of Risperdal augmented with Effexor XR may provide a better plan for management. Use of low dose Risperdal (since this agent has SSRI activity) augmented by Effexor XR should allow for reduction in anxiety as well as a more rapid approach to the severe depression. Success in this area will improve appetite…
Recommended tapering : Stop the 100mg AM and 25mg 4PM dose of Seroquel, DC Wellbutrin and Trazodone now and start Risperdal 0.5mg AM and Effexor XR 75mg HS x 5 days, then reduce Seroquel to 100mg HS and increase Effexor XR to 150mg HS x 5 days and at that time DC Seroquel and increase the Effexor XR to 225mg HS..
After reaching 225mg Effexor XR at bedtime begin reduction of Restoril by decreasing to 15mg at bedtime for 30 days…. Monitor for need to titrate Effexor XR to 300mg HS… Then taper Restoril to 7.5mg q other HS for 30 days and D/C
Potential Savings: Seroquel cost $ 328.97 - Risperdal cost $ 101.82 = $ 227.15
Actual Savings from change: approved change to Risperdal $ 227.15

Potential savings from trazodone & Wellbutrin DC eventual DC of

Restoril starting Effexor and titrating upwards:

$ 303.28 - Effexor XR 225mg $ 198.98 = $ 104.30

Actual: Restoril was changed to prn and change to Effexor was made

Savings = $ 104.30

Tramadol 50mg tablets 1 tab po bid 6-8-05

Since the patient is requiring hydrocodone there is questionable efficacy for this medication.
Recommendation:
D/C tramadol now.
Potential Savings: $ 33.98
Actual Savings from change: $ 33.98

Vitamin C 500mg tablets 1 tab po q day 6-8-05 Recommendation: No changes

Wellbutrin XL 300mg tablet 1 tab po q day 6-8-05

See above

Avandia 4mg tablet 1 tab po q day 6-8-05

Although there is no HgbA1C available recent FBS on the CMP was low at 69. Weight loss is commonly seen with Glucophage while the patient is still above ideal body weight concomitant use of these two agents may reduce appetite. The possibility of frequent low plasma glucose levels would indicate the use of oral monotherapy until appetite improves. The lower plasma glucose levels could be worsening anxiety, mood swings and depression.
Recommendation: Response no change in Avandia dose DC’dGlucophage
D/C Glucophage and get an A1C now and q 3 months.
Potential Savings: $ 46.99 Actual Savings from change: $ 46.99

Furosemide 40mg tablet 1 tab po q day 6-8-05

Furosemide has a short 2 hour half life thus the body has 22 hours each day for a antidiuretic rebound response. This means that over a period of time more and more furosemide is needed to meet the patient’s needs. Use of long acting 24 hour half-life torsemide won’t allow for the rebound effects so dosing can remain low sparing more Potassium and Calcium. D/C Lasix start Demadex 20mg daily and DC KCL. No change
Potential Savings: $39.59 Actual Savings from change: $0.00

Protonix 40mg tablet 1 tab po hs 6-8-05

Continuous use of proton pump inhibitors can lead to serious complications especially in an institutionalized patient. The continuous use increases the risk of C. difficile diarrhea.
Recommendation:
DC Protonix & start H2 blocker utilize short term as described below.
Use of H2 blockers in a step-down approach may work well and reduce the potential for serious adverse events, additionally, allowing the pH to rise and establish a continuous basic media. This stops many drugs from being adequately absorbed and therefore results in an erratic response. Elevating the head of the bed by 25 to 30% as well as prohibiting spicy and difficult to digest foods after evening meal around 6 to 7 PM and consuming 3 oz buttermilk and saltine crackers or a container of plain yogurt amazingly helps this problem.. If these non-drug approaches are successful with this patient then the H2 blocker can be tapered away. Ranitidine 75mg bid until success can be seen from the non-drug approach then titrating down to 75mg HS for a month or two then q other HS for a month or two then D/C
Potential Savings: $111.12 - otc Zantac 21.59 = $ 89.53
Actual Savings from change: $ 89.53

Depakote 500mg capsule 1 cap po bid 6-8-05

With an albumin of 2.6 use of this highly protein bound drug can lead to failed therapy and increase side effect risk. Use of Topamax provides a better alternative.
Recommendation:
Start with Topamax 25mg HS for 7 days and titrate upwards in 25mg increments every 7 to 10 days until improvements are seen in mood and anxiety or dose of 200mg daily is reached. Topamax is only about 10 to 15% protein bound so low albumins will not be significant as they are with the Depakote. Depakote as with most anti-seizure drugs works by elevating the seizure threshold, Topamax works by stopping the misfires. Response: No change - reason causes weight loss
Potential Savings: $ 123.99 - Topamax $ 56.10 = $ 67.89
Actual Savings from change: $ 0.00 No changes made

Zinc sulfate 220mg tablet 1 tab po q day 6-8-05
Recommendation: DC Patient has no Zinc deficiency nor wounds long term use of Zinc is not necessary reserve if wound healing therapy is needed again in the future
Potential savings $ 5.00 no changes made no savings

Magnesium Oxide 440mg tablet 1 tab po bid 6-8-05

Support for the use of this agent isn’t found in the chart. With current respiratory problems it may exacerbate respiratory depression.
Recommendation:
DC Magnesium Oxide Response : No change
Potential Savings: $ 5.00 Actual Savings from change: $ 0.00 No changes made

DHEA 50mg tablet 1 tab po bid 6-8-05

Recommendation:
Consider stopping this drug since Depo-testosterone is being used. Recently his testosterone levels were elevated but the last values showed it at upper normal. Elevated levels can worsen depression induce paresthesias, cause insomnia and long term high dose use can lead to hepatotoxicity. Response: no change
Potential Savings: $10.00 Actual Savings from change: $ 0.00 No changes made

Glucophage 500mg tablet 1 tab po bid 7-5-05

Recommendation:
D/C metformin Glucophage DC’d
Potential Savings: see above Actual Savings from change: see above

KCL 20mEq tablet 1 tab po bid 7-1-05

With a Serum K of 4.4 and on supplements that supply some Potassium and if we change to torsemide KCL could be discontinued . Some question as to whether or not the KCL is being absorbed because of the basic stomach. Recommendation:
D/C KCL Response: No change
Potential Savings: $ 39.59 Actual Savings from change: $ 0.00

Trazodone 100mg tablet 1 tab po hs 7-5-05

D/C Trazodone DC’d
See above for savings

Miralax powder 1 capful po q day 7-21-05

Recommendation: No changes

Hydrocodone/APAP 10mg tablet 1 tab po qid 8-16-05

Quality of life is important and at 32 years of age he has a long time left. Pain management contributes significantly to enhancing quality of life.
Oral medication can result in peaks and troughs of therapy which are difficult to overcome. Use of Fentanyl patch would deliver a 24 hour a day pain control and reduce potential drug dependence to some degree. Starting with Fentanyl Patch 25mcg q 3 days and drop the Hydrocodone to 8AM, 4PM and 10PM daily for 9 days then evaluate for control and titrate the Fentanyl Patch 50mcg and reduce the Hydrocodone to 10PM only for 9 days, then stop all hydrocodone. (hold on to the hydrocodone for any breakthrough pain and use only PRN) then if breakthrough pain continues titrate to 75mcg patch q 3 days and wait and see… somewhere around these doses and in conjunction with the Effexor XR you should get continuous pain relief. RESPONSE: approved above
Potential Savings: Cost $ 59.99 - Patches cost $42.98 = $ 17.01
Actual Savings from change: $17.01

Arginaid 1 packet bid in OJ 8-16-05

After some of the above major changes are made if the patient still does not have an appetite then consider Marinol 2.5mg before lunch daily.. There has been some excellent successes from the use of this for appetite stimulation.
Response: No
No savings

Restoril 30mg capsule 1 cap po hs 9-29-05

See above for D/C of Restoril Changed to prn
Potential Savings: Actual Savings from change:

See above for savings

Depo-Testosterone 20mg/ml inj 75mg IM q week 9-29-05

After finishing other drug titrations we could consider reducing dose in 25mg increments each month until D/C Response: No change
Potential Savings: $ 101.99
Actual Savings from change: None no change made

Vitamin E 400IU capsules 1 cap po q day 12-30-05 Recommendation: No changes
Total Potential Savings: $ 622.55
Total Actual Savings: $ 354.30

Specific Drug information

Classification:
• Autonomic Agents
    • Sympathomimetics
        • Adrenergic agonists
• Respiratory Agents
    • Adrenergic agonists
        • Beta-agonists

Description, Mechanism of Action, Pharmacokinetics

Description: Albuterol is a moderately selective beta2-receptor agonist. Albuterol is a racemic mixture of R- and S-isomers, and is widely used as a bronchodilator. It is indicated for the management of asthma exacerbations or other chronic obstructive airway diseases. It is similar in structure to terbutaline, but exhibits less cardiac stimulation and more prolonged bronchodilation than isoproterenol or metaproterenol. Albuterol was originally approved by the FDA in 1981. Outside the US, albuterol is referred to as salbutamol. The R-isomer of albuterol is commercially available as levalbuterol nebulizer solution (see Levalbuterol monograph). The FDA issued an approvable letter for albuterol HFA breath-activated aerosol inhaler during August 2004.

Mechanism of Action: Albuterol is a moderately selective beta2-adrenergic agonist that stimulates receptors of the smooth muscle in the lungs, uterus, and vasculature supplying skeletal muscle. Albuterol is racemic beta-agonist, comprised of an equal mixture of R- and S-isomers. The R-isomer, known as levalbuterol, is primarily responsible for bronchodilation. Although not confirmed during clinical trials, the S-isomer of albuterol has bronchoconstrictive properties in animal models.

Intracellularly, the actions of albuterol are mediated by cyclic AMP, the production of which is augmented by beta2-stimulation. Albuterol is believed to work by activating adenylate cyclase, the enzyme responsible for generating cyclic AMP, an intracellular mediator. Increased cyclic AMP leads to activation of protein kinase A, which inhibits phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. The net result of beta2-receptor agonism in the lungs is relaxation of bronchial and tracheal smooth muscles, which in turn relieves bronchospasm, reduces airway resistance, facilitates mucous drainage, and increases vital capacity.

Albuterol can also inhibit the degranulation and subsequent release of inflammatory autocoids from mast cells. Stimulation of beta2-receptors on peripheral vascular smooth muscle can cause vasodilation and a modest decrease in diastolic blood pressure. Albuterol is an effective adjunctive treatment for hyperkalemia; beta2-adrenergic stimulation results in intracellular accumulation of serum potassium due to stimulation of the Na/K ATPase pump, leading to moderate degrees of hypokalemia.

Pharmacokinetics: Albuterol can be administered as oral tablets or oral solution, but is more commonly administered by oral inhalation. Following oral inhalation, albuterol is absorbed over several hours from the respiratory tract. It is postulated from studies with other inhaled bronchodilators that most of an albuterol inhaled dose (approximately 90%) is actually swallowed and absorbed through the GI tract. Onset of bronchodilation occurs within 5—15 minutes after oral inhalation, peaks in 0.5—2 hours, and lasts 2—6 hours. Administration via nebulization does not appear to significantly alter the pharmacokinetics of albuterol. When administered orally, albuterol is well absorbed through the GI tract. Onset of action begins within 30 minutes, peak levels are reached in 2—3 hours, and duration of action is 4—6 hours for the conventional-release tablets and 8—12 hours for the sustained-release product.

Albuterol crosses the blood-brain barrier and may cross the placenta. The liver metabolizes albuterol extensively to inactive compounds. Excretion of albuterol occurs through the urine and feces. After oral inhalation, 80—100% of a dose is excreted via the kidneys within 72 hours; up to 10% may be eliminated in feces. After oral administration, 75% of a dose is excreted in urine within 72 hours as metabolites; 4% may be found in feces. The elimination half-life of albuterol ranges from 2.7—6 hours, with orally administered albuterol having a shorter half-life than the inhaled product.

Description, Mechanism of Action, Pharmacokinetics last revised 12/29/2004 2:21:00 PM

Indications

• acute bronchospasm	• bronchospasm prophylaxis
• asthma	• hyperkalemia†

† non-FDA-approved indication

Dosage

For the treatment of acute bronchospasm or prevention of bronchospasm (bronchospasm prophylaxis) in patients with asthma:
NOTE: In general, regularly scheduled, daily use of short-acting beta2-agonists such as albuterol is not recommended to prevent asthmatic bronchospasm.[1515] For the prevention of bronchospasm due to asthma, the scheduled use of longer-acting beta-agonists is preferred (e.g., salmeterol or formoterol); concurrent inhaled or systemic corticosteroid therapy may be indicated.
Oral dosage (albuterol immediate-release tablets or oral solution):
Adults and adolescents: 2—4 mg PO every 6—8 hours (max: 32 mg/day).
Elderly: 2 mg PO every 6—8 hours (max: 32 mg/day).
Children 6—12 years: 2 mg PO every 6—8 hours (max: 24 mg/day).
Children < 6 years: Initially, 0.1 mg/kg PO every 8 hours, not to exceed 8 mg/day. If an adequate response is not obtained, this dose may be increased to 0.2 mg/kg PO every 8 hours (max: 12 mg/day).
Oral dosage (albuterol extended-release tablets):
NOTE: 2 mg immediate-release PO every 6 hours = 4 mg extended-release PO every 12 hour. In general, inhaled long-acting beta-agonists are preferred since they are longer-acting and have fewer side effects than oral sustained-release agents.
Adults and adolescents >= 12 years: 4—8 mg PO every 12 hours (max: 32 mg/day).
Children 6—11 years: Initially, 4 mg PO every 12 hours, not to exceed 8 mg/day. If an adequate response is not obtained, this dose may be increased in a stepwise fashion carefully, not to exceed 12 mg PO every 12 hours (max: 24 mg/day).
Children < 6 years: Do not use extended-release dosage.
Oral inhalation dosage (albuterol metered-dose inhaler):
Adults and children >= 4 years: 90—180 mcg (1—2 puffs) every 4—6 hours prn. Some clinicians recommend separating inhalations by up to 20 minutes to ensure bronchial penetration. For the acute treatment of severe episodes, 4—8 puffs every 20 minutes for up to 4 hours, then 4—8 puffs every 1—4 hours as needed.[1515]
Oral inhalation dosage (albuterol nebulizer solution):
Adults and adolescents: 2.5 mg every 6—8 hours prn delivered over 5—15 minutes. For the acute treatment of severe episodes, 2.5—5 mg initially every 20 minutes for 3 doses, then 2.5—10 mg every 1—4 hours as needed, or 10—15 mg/hour by continuous nebulization.[1515]
Children: 1.25—2.5 mg every 4—6 hours prn delivered over 5—15 minutes. For the acute treatment of severe episodes, 0.15 mg/kg (2.5 mg minimum, 5 mg maximum) every 20 minutes for 3 doses, then 0.15—0.3 mg/kg (10 mg maximum) every 1—4 hours, as needed, or 0.5 mg/kg/hour by continuous nebulization.[1515]
Infants and neonates: 0.05—0.15 mg/kg/dose every 4—6 hours prn delivered over 5—15 minutes.
Oral inhalation dosage (Accuneb™ albuterol nebulizer solution):
Adolescents and children >= 2 years: The usual dose is 0.63—1.25 mg administered by nebulization 3—4 times per day, as needed for the relief of bronchospasm in patients with asthma. Deliver over 5—15 minutes. More frequent administration is not recommended. Accuneb™ has not been studied in the setting of acute attacks of bronchospasm. Higher doses (e.g., 2.5 mg) may be needed in patients with acute exacerbations of bronchospasm, especially in children aged >= 5 years.
•for bronchospasm prophylaxis (to prevent exercise-induced bronchospasm):
Oral inhalation dosage (albuterol metered-dose inhaler):
Adults and adolescents: For the prevention of exercise-induced bronchospasm, two puffs (180 mcg) should be inhaled at least 15 minutes prior to exercise.[1221]

For the adjunctive emergency acute treatment of hyperkalemia† until hemodialysis is available:
NOTE: Albuterol treats hyperkalemia through beta-adrenergic stimulation of cellular potassium (K+) uptake. However, it is a temporary adjunctive measure.
Oral inhalation dosage (albuterol nebulizer solution):
Adults†: Single doses of 10 to 20 mg have been administered. K+ concentrations begin to fall within 30 minutes of administration, and may remain depressed up to 300 minutes when albuterol is nebulized.[7353] Levalbuterol (see Levalbuterol monograph) is also reported effective; however, it is usually more costly.[7354]
Children†: Nebulized albuterol 2.5 mg if weight < 25 kg and nebulized albuterol 5 mg if weight > 25 kg have been reported effective.[7355]
Premature neonates†: 400 mcg via nebulization has been reported effective.[7356]

Maximum Dosage Limits:
•Adults: 32 mg/day PO; oral inhalation maximum dependent on formulation used.
•Elderly: 32 mg/day PO; oral inhalation maximum dependent on formulation used.
•Adolescents: 32 mg/day PO; oral inhalation maximum dependent on formulation used.
•Children 6—12 years: 24 mg/day PO; oral inhalation maximum dependent on formulation used.
•Children < 6 years: Generally 12 mg/day PO; oral inhalation maximum dependent on formulation used.
•Infants: Individualize dosage.

Patients with hepatic impairment:
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Indications...Dosage last revised 8/15/2005 11:34:00 AM

Administration Guidelines

Oral Administration
•All dosage forms: Administer with meals to minimize gastric irritation.
•Oral solution: Administer using a calibrated measuring device.
•Storage of immediate release albuterol tablets and syrups: Store at controlled room temperature, preferably between 2—25 degrees C (36—77 degrees F). Protect from light.
•Extended-release tablets: Swallow whole, do not chew or crush. Storage: Volmax® extended-release tablets should be stored under refrigeration 2—8 degrees C (36—46 degrees F).

Inhalation Administration
•There are many different dosage forms of albuterol for inhalation.

Aerosol inhalation (metered-dose inhalers):
•Instruct patient on proper inhalation technique (see Patient Information). Make sure the canister is firmly seated in the plastic mouthpiece adapter before each use. Shake the inhaler well. It is recommended to prime the inhaler. Do this by spraying four times into the air, away from the eyes and face, before using for the first time. When the inhaler has not been used for a period of at least 4 days, prime by spraying two times into the air.
•If the patient is using other inhalers, instruct them to use albuterol first and wait 5 minutes, then use other inhalers as directed.
•A tube spacer extension may be beneficial in patients unable to coordinate inhalation and actuation.
•Following administration, instruct patient to rinse mouth with water to minimize dry mouth.
•To avoid the spread of infection, do not use the inhaler for more than one person.
•Storage: Store albuterol aerosol inhalation canisters at controlled room temperature, preferably between 15—30 degrees C (59—86 degrees F). The contents are under pressure and may burst when exposed to high environmental temperatures. Bring canisters to room temperature before use to ensure proper actuations.

Inhalation solution for nebulization:
•For a 2.5 mg dose of albuterol, dilute 0.5 ml of a 0.5% albuterol solution for nebulization to a final volume of 3 ml with NS or use 3 ml of the commercially available 0.083% albuterol solution for nebulization. Deliver solution by nebulization over 5—15 minutes.
•Storage: Store albuterol nebulizer solution products at controlled room temperature or refrigeration, preferably between 2—25 degrees C (36—77 degrees F), and below 40 degrees C (104 degrees F). Do not freeze. Protect from light. Keep container tightly closed. Keep nebulizer solutions that come within a foil package in the foil package until time of use.

Administration last revised 4/1/2004 3:23:00 PM

Contraindications/Precautions

• albuterol hypersensitivity	• hyperthyroidism
• angioedema	• hypokalemia
• levalbuterol hypersensitivity	• pheochromocytoma
• acute bronchospasm	• pregnancy
• breast-feeding	• QT prolongation
• cardiac arrhythmias	• seizure disorder
• cardiac disease	• seizures
• children	• status asthmaticus
• coronary artery disease	• tachycardia
• diabetes mellitus	• thyrotoxicosis
• elderly	• torsade de pointes
• hypertension

• Absolute contraindications are in italics.

Albuterol is absolutely contraindicated in patients with a known racemic albuterol hypersensitivity or hypersensitivity to related drugs (e.g., levalbuterol hypersensitivity), to propellant fluorocarbons, or to any component of the specific dosage formulation. Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. Like other inhaled beta-agonists, albuterol inhalational solution can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, albuterol inhalational solution should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.

Albuterol should be used with caution in patients with cardiovascular disorders including ischemic cardiac disease (coronary artery disease), hypertension, cardiac arrhythmias, tachycardia, or QT prolongation. In addition, beta-agonists should be avoided in patients with congenital long QT syndrome due to the risk of torsade de pointes.[4951] Significant changes in systolic and diastolic blood pressures and heart rate could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. As with other beta-adrenergic agonist medications, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Correct pre-existing hypokalemia prior to beta-agonist administration.

Elderly patients may be more sensitive to the side effects of beta-agonists, especially tremor and tachycardia; this risk is higher in patients with preexisting coronary artery disease. Although not clearly established, airway responsiveness to beta-agonist medications may also change with age.

Albuterol also should be used cautiously in patients with hyperthyroidism (thyrotoxicosis, thyroid disease), pheochromocytoma, unusual responsiveness to other sympathomimetic amines, or a seizure disorder (history of seizures).

Albuterol should be used with caution in patients with diabetes mellitus. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

If the patient needs more doses of albuterol inhalational solution than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen. Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If deterioration of asthma occurs during therapy with albuterol (e.g., acute bronchospasm, status asthmaticus), appropriate evaluation of the patient and the treatment strategy is warranted, giving special consideration to the possible need for corticosteroid therapy. Albuterol has no antiinflammatory activity and is not a substitute for inhaled or oral corticosteroid therapy. The use of beta-agonists alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents (e.g., corticosteroids) to the therapeutic regimen. Corticosteroids should not be stopped or reduced when albuterol therapy is instituted. Do not exceed recommended dosages of beta-agonists; fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

Albuterol is classified as a pregnancy risk category C drug since its safe use during pregnancy has not been established. Furthermore, beta-agonists can interfere with uterine contractility as a result of its beta-adrenergic-mediated relaxant effects on smooth muscle (oral > inhalation). Use during pregnancy only if the potential benefit justifies the potential risk.

It is not known if albuterol is excreted into breast milk. Plasma levels of albuterol after inhalation of therapeutic doses are very low in humans, but it is not known whether albuterol is excreted in human milk. Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of albuterol solution by nursing mothers, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of albuterol conventional-release tablets has not been established for children below the age of 6 years and of the extended-release product below the age of 12 years. The safety and effectiveness of albuterol syrup has not been established for children under the age of 2 years. A spacer device is recommended for use with metered-dose inhalers. Some children < 5 years may have difficulty using a metered-dose or powder inhaler device correctly, and the use of an inhalation solution may be more appropriate. The safety and effectiveness of has not been established in children < 2 years for oral inhalation of albuterol via nebulizer.

Contraindications last revised 5/2/2004 6:12:00 PM

Drug Interactions

• Amoxapine		• Haloperidol
• Arsenic Trioxide		• Levofloxacin
• Astemizole		• Levomethadyl
• Atomoxetine			Loop diuretics
• Bepridil		• Maprotiline
	Beta-agonists	• Methadone
	Beta-blockers		Monoamine oxidase inhibitors (MAOIs)
• Caffeine		• Moxifloxacin
• Chloroquine		• Norfloxacin
• Ciprofloxacin		• Ofloxacin
• Cisapride		• Pentamidine
• Clarithromycin			Phenothiazines
	Class IA antiarrhythmics	• Pimozide
	Class III antiarrhythmics	• Probucol
	Corticosteroids	• Procarbazine
• Digoxin		• Propafenone
• Droperidol		• Risperidone
• Erythromycin		• Sertindole
• Flecainide		• Sparfloxacin
• Furazolidone			Sympathomimetics
• Gatifloxacin		• Terfenadine
• Gemifloxacin		• Theophylline, Aminophylline
• Green Tea			Thiazide diuretics
• Grepafloxacin			Thyroid hormones
• Guarana			Tricyclic antidepressants
• Halofantrine		• Ziprasidone
	Halogenated anesthetics

If asthma symptoms occur between the use of long-acting beta-agonists (e.g., salmeterol or formoterol), short-acting beta2-agonists (e.g., albuterol) may be used safely for the symptomatic relief of acute asthma symptoms.[5197] [5262] When beginning treatment with a long-acting beta-agonist, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular, scheduled use of these drugs and use them only for the symptomatic relief of acute asthma symptoms. Patients should be cautioned that increasing short-acting inhaled beta2-agonist use is a signal of deteriorating asthma. Due to the pharmacology of albuterol [5262], the concomitant use of albuterol with other short-acting beta-agonists or short-acting sympathomimetic aerosol bronchodilators is NOT recommended due to the increased risk of adverse cardiovascular effects (considered duplicate therapy). Caution and close observation should also be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.[5262]

Albuterol and beta-blockers are pharmacologic opposites, and will counteract each other when given concomitantly.[5262] Beta-blockers may also lead to severe bronchospasm in asthmatic patients. Concurrent use of beta-blockers and albuterol should be avoided.[5262] However, if no acceptable alternative exists, a cardioselective beta-blocker (i.e., atenolol, metoprolol) may be used with caution.[5262]

Beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors (MAOIs).[5262] MAOIs may potentiate the actions of beta-agonists on the peripheral vasculature, which can result in severe hypotension. Although no data are available, drugs with MAOI activity such as furazolidone [5343] and procarbazine [5356] may interact similarly. Close observation for such effects is prudent, particularly if beta-agonists are administered within two weeks of stopping the MAOI.[5262]

Beta2-agonists, should be administered with caution to patients being treated with tricyclic antidepressants.[5262] Tricyclic antidepressants may potentiate the actions of beta-agonists on the peripheral vasculature, which can result in hypotension. Rarely, tricyclic antidepressants (TCAs) can potentiate QT prolongation when administered with beta-agonists, especially in the setting of beta-agonist-induced hypokalemia.[5252]

Based on the cardiovascular stimulatory effects of sympathomimetic drugs,[6289] the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Combined use of these agents may further increase this risk.

Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days.[5262] The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol or levalbuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol or levalbuterol therapy.[5262]

Non-potassium sparing diuretics, such as loop diuretics and thiazide diuretics may potentiate hypokalemia and ECG changes seen with beta-agonists such as albuterol.[5262] Hypokalemia due to beta-agonists appears to be dose-related. Caution is advised when loop or thiazide diuretics are coadministered with high doses of beta-agonists; potassium levels may need to be monitored.[5262]

Drugs known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Beta-agonists may be associated with adverse cardiovascular effects including QTc interval prolongation, usually at higher doses and/or when associated with hypokalemia.[5038] [5047] [5262] In addition, beta-agonists should be avoided in patients with congenital long QT syndrome.[4951] Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval because the action of beta-agonists on the cardiovascular system may be potentiated.[5038] [5047] Drugs known to increase the QT interval include Class IA antiarrhythmics, Class III antiarrhythmics, flecainide, and propafenone. In addition to antiarrhythmic drugs, other drugs which may result in QT prolongation include: some antipsychotics (e.g., phenothiazines, pimozide, haloperidol, risperidone, sertindole, ziprasidone), amoxapine, arsenic trioxide, astemizole, bepridil, cisapride, chloroquine, clarithromycin, droperidol, halofantrine, halogenated anesthetics, erythromycin, levomethadyl, maprotiline, methadone, some quinolone antibiotics (e.g. ofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, norfloxacin, sparfloxacin), pentamidine, probucol, terfenadine, and tricyclic antidepressants. This list is not inclusive of all agents that may prolong the QT interval. Tricyclic antidepressants (TCAs) can also potentiate the vascular effects of beta-agonists.

Methylxanthine derivatives (e.g., theophylline, aminophylline [5277]) and corticosteroids [3085] may aggravate the hypokalemic effect that may be seen with beta-agonists.[5197] Consider checking potassium levels if clinically indicated. However, beta-agonists are commonly used in conjunction with aminophylline, theophylline, and corticosteroid therapy. In addition, concomitant use of beta-agonists with xanthines, such as theophylline, can cause additive CNS stimulation. Although theophylline (or aminophylline) may be used together with beta-agonists, some patients may experience sensations of tremor or nervousness with combined use. Concomitant use of drugs and herbals such as cocaine, caffeine, guarana, green tea, and other sympathomimetics (such as oral decongestants or ephedra, ma huang) with beta-agonists might result in additive CNS stimulation (e.g., tremor, insomnia) or cardiovascular effects (e.g., increased blood pressure and heart rate).

Cardiovascular adverse effects of beta-agonists, such as increased heart rate and blood pressure, have been shown to be potentiated by the coadministration of atomoxetine. Albuterol 600 mcg IV over 2 hours when combined with atomoxetine 60 mg twice a day for 5 days resulted in additional increases in heart rate and blood pressure over that seen alone with albuterol. Exercise caution if beta-agonists and atomoxetine are coadministered; consider monitoring heart rate and blood pressure initially.[5135] The interaction may be less likely with inhaled beta-agonists versus those given systemically.

Interactions last revised 4/1/2005 9:26:00 AM

Adverse Reactions

• anaphylactoid reactions	• hypokalemia
• angina	• hypotension
• angioedema	• insomnia
• anxiety	• irritability
• arrhythmia exacerbation	• maculopapular rash
• bronchospasm	• muscle cramps
• cough	• nausea/vomiting
• diaphoresis	• nightmares
• dizziness	• palpitations
• drowsiness	• peripheral vasodilation
• dyspepsia	• QT prolongation
• epistaxis	• restlessness
• excitability	• sinus tachycardia
• flushing	• ST-T wave changes
• headache	• syncope
• hoarseness	• throat irritation
• hostility	• tremor
• hyperglycemia	• urinary retention
• hyperkinesis	• urticaria
• hypertension	• xerostomia

The most common adverse reactions associated with albuterol use are related to its sympathomimetic effects, although certain cardiovascular effects may be less common with albuterol than with sympathomimetics that have less selectivity for beta2-adrenergic receptors. In general, the sympathomimetic effects of albuterol are dose-related and are more frequent with the oral tablets or syrup than with the inhalation aerosol or solution for inhalation. Like other sympathomimetics, albuterol can rarely cause adverse cardiovascular effects such as hypertension (3%), angina (<1%), palpitations, sinus tachycardia, or arrhythmia exacerbation or precipitation, especially in patients with preexisting cardiovascular disease. Although infrequent, peripheral vasodilation (hypotension, syncope) can also occur from beta2-stimulation of the vasculature. Albuterol can produce clinically significant cardiovascular effects in some patients, as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of albuterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, ST-T wave changes (e.g., flattening of the T wave, ST segment depression) and QT prolongation. Cardiac effects may be related to sympathomimetics effects and/or beta-agonist-induced hypokalemia. Albuterol can cause hyperglycemia and hypokalemia. Both of these effects occur from stimulation of beta2-receptors, resulting in gluconeogenesis and intracellular movement of potassium. These effects occur most commonly with inhalation (via nebulization) of relatively large doses of albuterol (e.g., 5—10 mg).

Anaphylactoid reactions have been rarely reported with beta-agonist therapy. Immediate hypersensitivity reactions may occur after administration of racemic albuterol, as demonstrated by rare cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, maculopapular rash, and urticaria. Use of albuterol inhalation solution produces adverse effects similar to those observed with the inhalation aerosol.

The most common adverse reactions associated with use of albuterol inhalation aerosol are palpitations (<10% of patients), sinus tachycardia (10%), anxiety (<10%), tremor (<15% of patients), and increased blood pressure (5%) occasionally resulting in hypertension. Other adverse effects include nausea/vomiting (6%), throat irritation (6%), dyspepsia (5%), insomnia (3%), headache (3%), epistaxis (3%), cough (2%), dizziness (1%), nightmares (1%), and hostility (1%). Dry mouth (xerostomia) or throat hoarseness may also occur following beta-agonist oral inhalation.

The most frequent adverse reactions to albuterol tablets or syrup are tremor (10—20%) and anxiety (9—20%). Other commonly reported reactions include headache (4—7%), sinus tachycardia and palpitations (2—5%), hyperkinesis (2—4%), dizziness (2—3%), muscle cramps (1—3%), insomnia (1—2%), nausea/vomiting (1—4%), and excitability (2%). Extended-release tablets may be associated with a lower incidence of anxiety, vomiting, and tremor than immediate-release tablets. Less frequent adverse reactions occurring in less than 1% of patients include flushing, drowsiness, restlessness, irritability, angina, cough, diaphoresis, and urinary retention. Some adverse effects appear to occur more frequently in young children (2—6 years of age) than in older children or adults; especially excitability and anxiety which occur in roughly 20% and 15% of young children, respectively. Gastrointestinal symptoms (e.g., nausea, vomiting) have been reported in about 2% of young children. These gastrointestinal effects are thought to result from sympathetic slowing of gut motility.

Adverse Reactions last revised 7/1/2002

Monitoring Parameters

Monitoring Parameters
•PFTs

Product Information

More information about the following products is available:
• Accuneb™
• Proventil®
• Proventil® HFA
• Respirol Rx™
• Salbutamol™
• Ventolin®
• Ventolin® HFA
• Ventolin® Syrup
• Volmax®
• VoSpire ER™
• Vospire ER®

Patient Education

Albuterol inhalation aerosol

What is albuterol inhalation aerosol?
ALBUTEROL (Proventil®, Ventolin®) is a bronchodilator, a medicine that opens up your air passages and makes breathing easier. It is a medicine for patients with various lung problems such as asthma and chronic bronchitis. Albuterol aerosol controls acute episodes or prevents recurring bouts of bronchospasm. It is useful for the prevention of exercise-induced bronchospasm. Generic albuterol inhalation aerosol is available.

What should my health care professional know before I use albuterol?
They need to know if you have any of the following conditions:
•diabetes
•heart disease, or irregular heartbeat
•high blood pressure
•low blood levels of potassium
•lung disease
•pheochromocytoma
•seizures (convulsions)
•thyroid disease
•an unusual or allergic reaction to albuterol, levalabuterol, sulfites, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?
Albuterol aerosol is for inhalation through the mouth. Make sure the canister is firmly seated in the plastic mouthpiece adapter before each use. Shake the inhaler well. Prime the inhaler by spraying four times into the air, away from the eyes and face. Do this before using for the first time and when the inhaler has not been used for at least 4 days. Tilt your head back slightly. Breathe out fully, emptying as much air as possible from your lungs. Keep the canister upright. Keep the inhaler about 1 inch from your open mouth (or place the mouthpiece loosely between your open lips). Press down on the inhaler (one puff) while breathing in deeply and slowly. Hold your breath for at least 10 seconds and then exhale (breathe out). Wait for at least 1 to 2 minutes between puffs. Do not use more often than directed.

For preventing exercise-induced bronchospasm: Do not forget to use your albuterol as directed 15 minutes before exercise.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What if I miss a dose?
For regular prevention of bronchospasm: If you miss a dose, use it as soon as you can. If it is almost time for your next dose, use only that dose. Do not use double or extra doses.

What drug(s) may interact with albuterol?
•arsenic trioxide
•astemizole
•bepridil
•beta-blockers, often used for high blood pressure or heart problems
•arsenic trioxide
•astemizole
•bepridil
•beta-blockers, often used for high blood pressure or heart problems
•caffeine
•certain antibiotics (such as clarithromycin, erythromycin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, linezolid, moxifloxacin, sparfloxacin)
•chloroquine
•cisapride
•droperidol
•halofantrine
•levomethadyl
•medicines for colds and breathing difficulties
•medicines for heart disease or high blood pressure
•medicines known as MAO inhibitors, such as phenelzine (Nardil®), tranylcypromine (Parnate®), isocarboxazid (Marplan®), and selegiline (Carbex®, Eldepryl®)
•medicines to control heart rhythm (examples: amiodarone, disopyramide, dofetilide, flecainide, procainamide, quinidine, sotalol)
•medicines for treating depression or mental illness (amoxapine, haloperidol, maprotiline, pimozide, phenothiazines, risperidone, sertindole, tricyclic antidepressants, ziprasidone)
•methadone
•pentamidine
•probucol
•some medicines for weight loss (including some herbal products, ephedra, ephedrine, dextroamphetamine)
•steroid hormones such as dexamethasone, cortisone, hydrocortisone
•terfenadine
•theophylline
•thyroid hormones
•water pills or diuretics

Tell your prescriber or health care professional about all other medicines you are taking, including nonprescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check before starting or stopping any of your medicines.

What side effects may I notice from taking albuterol?
Side effects that you should report to your prescriber or health care professional as soon as possible:
Rare:
•skin rash or hives
•swelling of the tongue, face, or lips with difficulty breathing, difficulty swallowing, hoarseness, or tightening of the throat (angioedema)
Infrequent:
•difficulty breathing or wheezing which increases or does not go away
•dizziness or fainting spell
•chest pain or palpitations (fast, pounding heartbeat)
•fast or irregular heartbeat
•fever
•headache (severe)
•increased blood pressure
•muscle cramps or weakness
•numbness in fingers or toes
•vomiting

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
•anxiety, nervousness, trembling
•cough
•diarrhea
•difficulty sleeping
•dry mouth
•mild headache
•nasal congestion, runny nose
•nausea, upset stomach
•throat irritation (mild)
•unusual taste

What should I watch for while taking albuterol?
Tell your prescriber or health care professional if your symptoms do not improve. If your asthma or bronchitis gets worse while you are using albuterol, call your prescriber or health care professional as soon as you can for advice.

Do not get the aerosol spray in your eyes.

If you are using other inhalers such as ipratropium (Atrovent) or an inhaled steroid such as beclomethasone (Beclovent) or triamcinolone (Azmacort), use albuterol first. Wait at least 5 minutes before using the other inhaler.

Make sure you are using your inhaler properly. Do not use extra or more frequent inhalations. They will not improve your condition. Once a day, remove the metal canister and rinse the plastic case in warm running water. Replace canister gently without using a twisting motion.

Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water, will help.

Where can I keep my medicine?
Keep out of the reach of children.

Store albuterol aerosol inhalation canisters at controlled room temperature, preferably between 15—30 degrees C (59—86 degrees F). The contents are under pressure and may burst when exposed to high environmental temperatures, heat or flame. Cold temperature decreases the effectiveness of albuterol. Do not freeze. Bring canisters to room temperature before use to ensure proper actuations. Throw away any unused medicine after the expiration date.

NOTE: This information is not intended to cover all possible uses, precautions, interactions, or adverse effects for this drug. If you have questions about the drug(s) you are taking, check with your health care professional.

[Revised: 05/02/2004]

Albuterol inhalation solution

What is albuterol inhalation solution?
ALBUTEROL (Proventil®, Ventolin®) is a bronchodilator, a medicine that open up your air passages and make breathing easier. Albuterol is used for patients with various lung problems such as asthma and chronic bronchitis. Regular use of albuterol inhalation controls recurring bouts of bronchospasm. Generic albuterol inhalation solution is available.

How should I use this medicine?
Albuterol inhalation solution is for use in a nebulizer. Nebulizers convert a solution of albuterol into an aerosol for inhalation through the mouth and into the lungs. The flow rate is adjusted to provide a correct dose. Follow the product instructions to prepare and administer the albuterol inhalation solution. Follow the directions for correct use of the nebulizer. Carefully read the product instructions provided; take precautions to avoid bacterial contamination of the albuterol dose or nebulizer system. Use doses at regular intervals. Do not use more often than directed.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What if I miss a dose?
If you miss a dose, use it as soon as you can. If it is almost time for your next dose, use only that dose. Do not use double or extra doses.

What should I watch for while taking albuterol?
Tell your prescriber or health care professional if your symptoms do not improve. If your asthma or bronchitis gets worse while you are using albuterol call your prescriber or health care professional as soon as you can for advice.

Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water, will help.

Where can I keep my medicine?
Keep out of the reach of children.

Store at controlled room temperature, preferably between 2—25 degrees C (36—77 degrees F), and below 40 degrees C (104 degrees F). Do not freeze. Protect from light. Keep container tightly closed. Keep nebulizer solutions that come within a foil package in the foil package until time of use. Throw away any unused medicine after the expiration date.

[Revised: 05/02/2004]

Albuterol oral syrup

What is albuterol oral syrup?
ALBUTEROL (Proventil®, Ventolin®) is a bronchodilator, a medicine that opens up your air passages and makes you breathe easier. It is a medicine for patients with various lung problems such as asthma and chronic bronchitis. Generic albuterol oral syrup is available.

What should my health care professional know before I take albuterol?
They need to know if you have any of the following conditions:
•diabetes
•heart disease, or irregular heartbeat
•high blood pressure
•low blood levels of potassium
•lung disease
•pheochromocytoma
•seizures (convulsions)
•thyroid disease
•an unusual or allergic reaction to albuterol, levalabuterol, sulfites, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I take this medicine?
Take albuterol oral syrup by mouth. Follow the directions on the prescription label. Shake well before using. Use a specially marked spoon or container to measure your medicine. Ask your pharmacist if you do not have one; household spoons are not always accurate. Do not take more often than directed.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check before starting or stopping any of your medicines.

What should I watch for while taking albuterol?
Tell your prescriber or health care professional if your symptoms do not improve in 1 or 2 days. If your asthma or bronchitis gets worse while you are using albuterol, call your prescriber or health care professional as soon as you can for advice.

Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water, will help.

Where can I keep my medicine?
Keep out of the reach of children.

Store at a room temperature between 2 and 30 degrees C (36 and 86 degrees F); do not freeze. Protect from light. Keep container tightly closed. Throw away any unused medicine after the expiration date.

[Revised: 05/02/2004]

Albuterol tablets or extended-release tablets

What are albuterol tablets or extended-release tablets?
ALBUTEROL (Proventil®, Ventolin®) is a bronchodilator, a medicine that opens up your air passages and makes you breathe easier. It is a medicine for patients with various lung problems such as asthma or chronic bronchitis. Generic albuterol tablets and extended-release tablets are available.

How should I take this medicine?
Take albuterol tablets or extended-release tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If albuterol upsets your stomach, take it with food or milk. Swallow extended-release tablets whole; do not crush or chew. Do not take more often than directed.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water, will help.

Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.

Store most tablets at controlled room temperature between 2 and 25 degrees C (36 and 77 degrees F). Volmax® extended-release tablets should be stored under refrigeration 2—8 degrees C (36—46 degrees F). Keep container tightly closed. Throw away any unused medicine after the expiration date.

[Revised: 05/02/2004]

Quetiapine
Seroquel®

Classification:
• Psychotropic Agents
    • Antimanics
• Psychotropic Agents
    • Antipsychotics
        • Atypical Antipsychotics

Description, Mechanism of Action, Pharmacokinetics

Description: Quetiapine is an atypical antipsychotic agent structurally similar to clozapine, a dibenzodiazepine antipsychotic. Atypical antipsychotics are deemed to be the standard of care for schizophrenia and related disorders, and with the exception of clozapine, may be considered as first-line treatment options for the management of psychosis. Like clozapine, quetiapine has been shown to improve positive and potentially negative symptoms of schizophrenia without producing extrapyramidal side effects. The effect of quetiapine on the positive and negative symptoms of schizophrenia has been shown to be equivalent to haloperidol. However, unlike typical antipsychotic agents such as haloperidol, quetiapine is not associated with significant extrapyramidal symptoms and does not cause persistent elevations of serum prolactin concentrations in humans; thus, it may be associated with a lower incidence of adverse effects due to hyperprolactinemia (e.g. galactorrhea, amenorrhea). Additionally, quetiapine was not associated with agranulocytosis during initial clinical trials. Clinical trials indicate that quetiapine is effective as monotherapy for the management of bipolar mania; treatment may also be delivered in combination with standard mood stabilizers (i.e., lithium, divalproex).[7391] The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study evaluated the effectiveness of selected atypical antipsychotics and perphenazine in schizophrenic patients (see Atypical Antipsychotic Overview).[8303] Quetiapine trials also suggest effectiveness in the treatment of the depressive phase of bipolar disorder.[7349] [7419] Quetiapine received FDA approval for management of the manifestations of psychotic disorders in September 1997. Quetiapine (as monotherapy or in combination with lithium or divalproex) received FDA approval for manic episodes associated with bipolar disorder on January 13, 2004. The manufacturer is currently investigating the use of quetiapine as monotherapy for major depressive disorder.

In August 2004, the FDA requested all manufacturers of atypical antipsychotics to include revised product label warnings about the potential for an increased risk of hyperglycemia and diabetes with the use of atypical antipsychotics.

On April 11, 2005 the FDA issued a public health advisory noting that the unapproved use of atypical antipsychotics for the treatment of behavioral disorders in the elderly with dementia has been associated with a higher death rate vs. placebo. All manufacturers of atypical antipsychotics will be required to include a boxed warning in their labeling noting this risk.

Mechanism of Action: Similar to clozapine, quetiapine is a potent serotonin 5-HT2-receptor antagonist with moderate dopamine (D2)-receptor antagonism. The antipsychotic action is believed to be mediated through a combination of dopamine D2 and serotonin 5-HT2 receptor antagonism. Having a greater occupancy at 5-HT2 receptors relative to D2 receptors is a feature of atypical antipsychotic drugs and may explain, in part, the lower propensity of these agents to cause extrapyramidal side effects. The selectivity of quetiapine for dopamine receptors on mesolimbic neurons rather than nigrostriatal neurons also helps to explain its atypical profile. Quetiapine also antagonizes other receptors in the brain, including serotonin 5-HT 1a, dopamine D1, histamine H1, and adrenergic alpha1 and alpha2 receptors; it has no appreciable activity at cholinergic, muscarinic and benzodiazepine receptors. Orthostatic hypotension observed with use of quetiapine may be a result of alpha1 antagonism, while somnolence is likely a result of histamine H1 antagonism.

Dopamine (D2)-receptor blockade in the tuberoinfundibular tract results in prolactin release, which can lead to adverse effects such as amenorrhea and galactorrhea. Although both haloperidol and quetiapine produce acute increases in serum prolactin concentrations in rats, the elevated prolactin concentrations produced with quetiapine decline rapidly over time while those produced by haloperidol remain elevated. In clinical trials with humans, quetiapine did not produce sustained elevations of serum prolactin, which may account for the lack of significant prolactin-related side effects.

Pharmacokinetics: Quetiapine is administered orally. After oral administration, quetiapine is rapidly absorbed, with peak plasma concentrations achieved in about 1.5 hours. Food increases Cmax and AUC by 25% and 15%, respectively. Quetiapine is widely distributed throughout the body with a volume of distribution of about 10 L/kg. About 83% of the drug is bound to plasma proteins at therapeutic concentrations. Quetiapine is extensively metabolized by the liver, with less than 1% of the dose excreted as unchanged drug. Major metabolites include an inactive sulfoxide metabolite thought to be produced by the cytochrome P450 3A4 isoenzyme and a parent acid metabolite produced by oxidation. Oral clearance of quetiapine is reduced by about 40% in elderly patients compared with young patients. Patients with hepatic insufficiency or severe renal impairment (CrCl 10—30 ml/min) have a 30% and 25% lower mean oral clearance, respectively, than normal subjects. The mean half-life of quetiapine is roughly 6 hours in patients with normal renal and hepatic function.

Description, Mechanism of Action, Pharmacokinetics last revised 11/1/2005 10:56:00 AM

Indications

• agitation†	• mania
• bipolar disorder	• obsessive-compulsive disorder (OCD)†
• dementia†	• schizophrenia

† non-FDA-approved indication

Dosage

For the treatment of psychotic disorders (e.g., schizophrenia, schizoaffective disorders, psychotic depression, etc.):
NOTE: Reinitiation of quetiapine after discontinuation of < 1 week may occur at the same dose/schedule without titration. If therapy has been stopped for > 1 week, follow initial titration schedule.[5855]
•for the oral treatment of psychotic disorders in outpatients or hospitalized patients:
Oral dosage:
Adults (not at risk for hypotension): Initially, 25 mg PO twice daily. Increase by 25—50 mg PO 2—3 times per day on the 2nd and 3rd day, as tolerated, to a target range of 300—400 mg/day by the 4th day, given in 2—3 divided doses. Further dosage increments, if indicated, should generally occur not less than every 2 days. The maximum effective dose of quetiapine has not been established. Doses of 150—750 mg/day were used in clinical trials. In one dose-ranging study, doses above 300 mg/day were no more efficacious than a 300 mg/day dose. In other studies, however, doses in the range of 400—500 mg/day were needed. The safety of doses above 800 mg/day has not been evaluated. The antipsychotic efficacy of quetiapine was established in short-term (6 week) controlled trials in inpatients with schizophrenia. Long-term use has not been systematically evaluated.[5855]
Elderly, debilitated patients, and patients at risk for hypotension: Initially, 25 mg PO twice daily, see adult dosage titration. A slower rate of titration and a lower target dose should be considered.
Adolescents and children: Safe and effective use has not been established.
•for the treatment of severe behavioral disturbances (e.g., agitation†, aggression, psychosis, etc.) due to organic brain syndromes† or dementia†, such as those with Alzheimer's disease, late-stage Parkinson's disease, or dementia with Lewy bodies:
NOTE: The labeling of all atypical antipsychotics contains a Black Box Warning noting an increased risk of death (roughly 1.7 times greater than placebo) in the elderly patient being treated for behavioral problems associated with dementia. Atypical antipsychotics are not approved for the treatment of behavioral problems associated with dementia (see Contraindications).
Oral dosage:
Elderly: Initially, 25 mg PO twice daily. Dosage adjustments of 25—50 mg twice per day, if indicated, should occur at intervals of not less than 2—7 days. The maximum effective dose has not been established. Federal OBRA guidelines for nursing homes recommend the dosage not exceed 200 mg/day PO administered in 2—3 divided doses, except when higher doses are necessary to maintain or improve the resident's functional status. Titrate slowly and use with caution in elderly at risk for hypotension.

For short-term monotherapy or for adjunctive treatment with mood stabilizers (e.g., lithium or divalproex) of acute mania associated with bipolar disorder (bipolar I disorder) with or without psychotic features:
NOTE: Dosage must be individualized according to the degree of mental and emotional disturbance exhibited. In all cases, the lowest effective dosage should be determined for each patient.
NOTE: Reinitiation of quetiapine after discontinuation of < 1 week may occur at the same dose/schedule without titration. If therapy has been stopped for > 1 week, follow initial titration schedule.
NOTE: Manufacturer-sponsored clinical trials of quetiapine in bipolar disorder excluded patients with rapid cycling or mixed episodes; small, open label, add-on therapy studies have been performed in these populations. In a mean 112-day study of rapid cycling bipolar patients (n=14), patients received an initial 50 mg quetiapine dose in addition to their current therapy. Significant results included a -1.8 point for the Clinical Global Impression - Bipolar Disorder (p = 0.013), a -1.3 point for the mania subscale (p = 0.016), a -1.01 point for the YMRS (p = 0.025). Improvement in depressive symptoms was not significant. Adequate doses for acute episodes could significantly differ according to the presenting episode and the length of treatment. Doses of quetiapine were significantly reduced by the end of the study (mean dose 443 mg/day vs. 268 mg/day) and they also differed according to the initial episode to be treated (mean dose 720 mg/day for mania, 183 mg/day for depression). Seven of 14 patients stopped cycling with treatment.[7374]
Oral dosage:
Adults (not at risk for hypotension): Initially, 50 mg PO twice daily on Day 1, increase to 400 mg/day on Day 4 in increments of up to 100 mg/day given in divided doses twice daily. Further titration up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. Safety of doses > 800 mg/day not established.[4516] [5855] In two pivotal monotherapy trials (n=300, n=299) quetiapine was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12 at doses ranging from 400—800 mg/day. In a 3-week placebo-controlled trial, 170 patients with acute bipolar mania (YMRS >= 20) were randomized to receive quetiapine or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. Quetiapine was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. In a similarly designed trial (n=200), quetiapine was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo.[5855] In two 12-week, multicenter, double-blind studies of 302 bipolar I (manic episode) patients, quetiapine was shown to be superior to placebo in reduction of YMRS scores from day 4 to 84, and equivalent to haloperidol or lithium by day 84.[7390] Efficacy as adjunctive treatment with lithium or divalproex, resulting in significant reduction in YMRS scores (-13.8 for quetiapine, -9.93 for placebo) from a baseline score of roughly 31 has been demonstrated.[7391] The mean quetiapine dose was 492 (+/-) 204 mg in another positive trial evaluation of lithium/divalproex adjunct therapy.[7395] The efficacy of quetiapine for depressive symptoms of bipolar disorder have been suggested in open-label trials.[7349] In an unpublished 8 week, double-blind, placebo-controlled study of bipolar I or II patients with current depression episode, patients randomized to quetiapine 300 mg/day (n=180) or 600 mg/day (n=181) demonstrated significantly greater improvement in MADRS and HAM-D scores from week 1 through study endpoint (vs. placebo; n=181). The quetiapine 300mg and 600 mg dose both improved MADRS scores by roughly -16.5 points vs. -10 points for placebo.[7419]
Elderly, debilitated patients, and patients at risk for hypotension: Consider 25 mg PO twice daily initially; see adult dosage titration. A slower rate of titration and lower target dose should be considered.[5855]
Adolescents†: In a 6-week, randomized, placebo-controlled trial, 30 adolescents (12—18 years) with mixed or manic bipolar disorder received an initial divalproex dose of 2 mg/kg/day PO and were randomized to 6 weeks of combination therapy with quetiapine (titrated to 450 mg/day) vs. placebo. The Young Mania Rating Scale (YMRS) score decreased and the response rate increased significantly in the quetiapine group at 6 weeks. A reduction in YMRS scores >/= 50% from baseline to endpoint was measured in 87% of quetiapine-treated patients and in 53% of placebo-treated patients. Sedation was more pronounced in the quetiapine group.[4517]
Children: Safe and effective use of combination therapy is not established.

For the adjunctive treatment of refractory obsessive-compulsive disorder (OCD)† (in combination with maximal OCD dose of a selective serotonin reuptake inhibitor [SSRI]):
NOTE: Reinitiation of quetiapine after discontinuation of < 1 week may occur at the same dose/schedule without titration. If therapy has been stopped for > 1 week, follow initial titration schedule.
Oral dosage:
Adults: Initially, 50 mg PO once daily; dose may be taken at bedtime. In a well-controlled clinical trial, the target dose of quetiapine after titration was 200 mg/day PO.[6971] At weeks 1—2, the dose was elevated to 100 mg/day PO; weeks 3—6, up to 200 mg/day. In weeks 7—8, a maximum of 300 mg/day PO was given if needed. Daily doses may be divided. Somnolence was the most common adverse event. In a placebo controlled, double blind study at week 6 (n=40, patients without comorbid disease), statistical significance was demonstrated in the Clinical Global Impressions-Improvement (CGI-I) score (mean CGI-I score of 2.9 quetiapine vs. 3.8 placebo). Eight out of 20 quetiapine patients were 'very much improved' or 'much improved' while in the placebo group 2/20 were 'much improved.' At week 4, the Young Brown Obsessive Compulsive Scale (Y-BOCS) scores were significant between groups. Two open-label studies [6974] [6975] and one single-blind, placebo-controlled study [6972] concur with the above results, while one open label study found negative results [6973]. Larger controlled clinical trials are needed to validate long-term efficacy, as well as effectiveness in patients with co-morbid disease states (i.e., depression, bipolar disorder, panic). A slower titration schedule may be required in patients at risk for hypotension.

Maximum Dosage Limits:
•Adults: Not definitive, 800 mg/day PO suggested. Debilitated and/or patients at risk for hypotension may require lower dosages.
•Elderly: Not definitive, 200—800 mg/day PO suggested. Debilitated and/or patients at risk for hypotension may require lower dosages.
•Adolescents: Safe and effective use has not been established.
•Children: Safe and effective use has not been established.

Patients with hepatic impairment:
Patients with hepatic impairment have a 30% lower mean clearance of quetiapine than normal subjects; dosage adjustment is necessary. Initially, give 25 mg PO on Day 1, and titrate in 25 or 50 mg/day increments to the lowest effective and tolerable dose.[5855]

Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available. Although patients with severe renal impairment (CrCl 10—30 ml/min) have a 25% lower mean clearance than normal subjects, plasma quetiapine concentrations are still within the range of concentrations seen in normal subjects receiving the same dose. Therefore, it appears that no dosage adjustment is needed in patients with a CrCl above 10 ml/min.[5855]

†non-FDA-approved indication

Indications...Dosage last revised 4/13/2005 9:57:00 AM

Administration Guidelines

Oral Administration
•Quetiapine may be administered without regard to meals.
•When restarting patients on quetiapine who have been off of the drug for more than one week, the initial titration schedule should be followed.

†non-FDA approved

Administration last revised 7/1/2002

†non-FDA-approved indication

Contraindications/Precautions

• brain tumor	• heart failure
• breast cancer	• hepatic disease
• breast-feeding	• hypotension
• cardiac disease	• hypothyroidism
• cataracts	• hypovolemia
• cerebrovascular disease	• myocardial infarction
• children	• obesity
• dehydration	• Parkinson's disease
• dementia	• pregnancy
• diabetes mellitus	• seizure disorder
• dysphagia	• suicidal ideation
• elderly

Quetiapine can cause orthostatic hypotension associated with dizziness, tachycardia, and in rare cases, syncope. Orthostatic hypotension is most likely to occur during the initial dosage titration period and is thought to be caused by alpha1-adrenergic blockade, resulting in peripheral vasodilation. Quetiapine should be used with caution in patients with pre-existing hypotension or cerebrovascular disease. This drug should also be used with caution in patients with cardiac disease, especially those with heart failure, a history of myocardial infarction or ischemia, or conduction abnormalities. Conditions that may predispose patients to hypotension, such as hypovolemia and dehydration, should be corrected, if possible, before starting quetiapine therapy. Lower doses may be required in patients at risk for hypotension.

Quetiapine was associated with the development of cataracts in animal studies. Lens changes have also been observed with long-term therapy in humans, however, a causal relationship has not been established. Nevertheless, examination of the lens by methods adequate to detect cataract formation is recommended upon initiation of quetiapine or shortly thereafter, and at six month intervals during chronic treatment.

Patients with schizophrenia may develop suicidal ideation. Therefore, close supervision and control of medication is advisable; prescriptions for quetiapine should be written for the smallest quantity of tablets possible to reduce the risk of overdose.

Quetiapine has been associated with dose-dependent decreases in total and free thyroxine (T4). Although most of these changes were not clinically significant, a few cases of clinically relevant hypothyroidism were reported. Patients should be monitored for signs and/or symptoms of hypothyroidism during treatment with quetiapine.

In epidemiological studies and case reports, atypical antipsychotics have been associated with elevations in blood glucose, decreased insulin sensitivity, and precipitation or unmasking of diabetes mellitus in susceptible patients (see Adverse Reactions). Patients with pre-existing diabetes mellitus should monitor their blood glucose levels and watch for signs of excessive urination, thirst, and hunger while taking atypical antipsychotics. Patients with risk factors for diabetes, such as obesity or a family history of diabetes should undergo fasting glucose testing at baseline and periodically throughout treatment. Patients developing signs or symptoms suggestive of diabetes while receiving an atypical antipsychotic should be tested for diabetes.

Quetiapine should be used cautiously in patients with dysphagia and in other patients at risk for aspiration pneumonia. Esophageal dysmotility and aspiration have been associated with other antipsychotic drugs. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Atypical antipsychotics are not approved for control of behavioral disorders in elderly patients with dementia. In April 2005 the FDA mandated that all manufacturers of atypical antipsychotics include a black box warning to the labeling noting that increased death rates (1.6—1.7 times that of placebo) have been noted in these patient populations receiving atypical antipsychotics. Death typically occurred due to heart failure, sudden death, or infections (primarily pneumonia). Of 17 placebo controlled trials (n=5106) performed with olanzapine, aripiprazole, risperidone, or quetiapine in elderly demented patients with behavioral disorders, 15 showed numerical increases in mortality in the active compared to the placebo-treated patients.

Quetiapine should be used with caution in patients with Parkinson's disease because of possible development of extrapyramidal symptoms.

In clinical trials with quetiapine, seizures occurred in a small number of patients (0.8%). For this reason, quetiapine should be used with caution in patients with a seizure disorder or with conditions that may lower the seizure threshold (e.g. brain tumor, cerebrovascular disease).

Somnolence is a commonly reported adverse effect of quetiapine. Ethanol should be avoided and other CNS depressants should be used with caution in patients taking quetiapine due to the potential for additive CNS effects.

Quetiapine is metabolized by cytochrome P450 enzymes. This drug should be used with caution in elderly patients and in patients with hepatic disease because of the possibility of reduced drug clearance; a slower rate of dose titration and a lower target dose should be considered.

Although quetiapine did not increase serum prolactin concentrations during clinical trials in humans, increased prolactin concentrations were observed in rat studies and were associated with an increase in mammary gland neoplasia. There is insufficient evidence linking chronic administration of antipsychotics with tumorigenesis in humans. However, because up to one-third of human breast cancer cases may be prolactin dependent (based on in vitro studies), quetiapine should be used with caution in women with breast cancer.

Quetiapine is classified as pregnancy category C. There are no adequate and well-controlled studies in pregnant women. However, when quetiapine was administered to rats or rabbits during the period of organogenesis, evidence of embryo/fetal toxicity was observed, including delays in skeletal ossification, minor soft tissue anomalies, and reduced body weight. In addition, maternal toxicity (decreases in body weight gain and/or death) was observed in these studies. Therefore, use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal studies have shown that quetiapine is excreted into breast milk; although this has not been established in humans, the drug should not be used in women who are breast-feeding.

The safe and effective use of quetiapine has not been established in children.

Contraindications last revised 4/13/2005 9:57:00 AM

Drug Interactions

	Antidiabetic Agents	• Ketoconazole
	Anti-retroviral protease inhibitors	• Leuprolide
	Anxiolytics, Sedatives, and Hypnotics	• Levodopa
• Aprepitant		• Lithium
	Barbiturates	• Lovastatin
• Bosentan		• Loxapine
• Bromocriptine		• Molindone
• Buprenorphine		• Nalbuphine
• Butorphanol		• Nicardipine
• Cabergoline		• Olanzapine
• Carbamazepine			Opiate agonists
• Cetrorelix		• Oxcarbazepine
• Cimetidine		• Pentazocine
• Clarithromycin		• Pergolide
• Dalfopristin; Quinupristin			Phenothiazines
• Danazol		• Phenytoin
• Delavirdine		• Pramipexole
• Diltiazem			Radiopaque Contrast Agents
• Dopamine		• Rifabutin
• Dronabinol, THC		• Rifampin
• Efavirenz		• Rifapentine
• Entacapone		• Risperidone
• Erythromycin		• Ropinirole
• Ethanol		• St. John's Wort, Hypericum perforatum
• Ethotoin		• Tolcapone
• Fluconazole		• Tramadol
• Fosphenytoin		• Triptorelin
• Ganirelix		• Troleandomycin
• Goserelin		• Valproic Acid, Divalproex Sodium
• Haloperidol		• Verapamil
• Imatinib, STI-571		• Voriconazole
• Itraconazole		• Zafirlukast

NOTE: The cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine. Quetiapine does not significantly induce hepatic enzymes responsible for cytochrome P450 mediated metabolism of antipyrine; quetiapine is not a known inhibitor of the cytochrome P450 enzyme system.[4718] [6458]

No significant drug interactions were identified when quetiapine was coadministered with fluoxetine or imipramine according to the manufacturer.[5855]

No significant drug interactions were identified when quetiapine was coadministered with lithium [5855] according to the manufacturer. However, patients receiving lithium and antipsychotics concomitantly should be closely monitored and the clinician should consider withdrawing one or both drugs if neurotoxicity becomes evident. An encephalopathic syndrome resembling Neuroleptic Malignant Syndrome (NMS) consisting of delirium, tremulousness, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevated serum enzymes, blood urea nitrogen and fasting blood sugar, followed by irreversible brain damage, has occurred when lithium was administered with some of the typical antipsychotic agents. Pharmacokinetically, quetiapine does not appear to alter serum lithium levels.[4233] [4234]

Concurrent use of quetiapine with other antipsychotics, like haloperidol [5036], loxapine [5355], molindone [5553], olanzapine [5517], risperidone [5144], and phenothiazines [5888], is not generally recommended. If used concomitantly with quetiapine, other antipsychotics may increase the risk of adverse effects such as drowsiness, sedation, dizziness, or orthostatic hypotension. Thioridazine [6443] increases the oral clearance of quetiapine by about 65%. The dosage of quetiapine may need to be increased if thioridazine is coadministered. No significant drug interactions were identified when quetiapine was coadministered with haloperidol or risperidone according to the manufacturer.[5855]

Coadministration of phenytoin and quetiapine increased the clearance of quetiapine by 5-fold.[6444] Increased doses of quetiapine may be required for control of psychotic symptoms when phenytoin or other hepatic enzyme inducers (e.g., barbiturates such as phenobarbital [4718], bosentan [4718], carbamazepine [4718], ethotoin [4718], fosphenytoin [4718], oxcarbazepine [4718], rifabutin [4718], rifampin [5550] [4718], rifapentine, or St. John's Wort [4728]) are administered concurrently.[4992] Also, caution is advised if a CYP3A4 enzyme-inducing drug is discontinued in a patient receiving quetiapine concomitantly. Two case reports indicate that quetiapine, when started after carbamazepine therapy [4084], may lead to elevated levels of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine. In each case, the CBZ-E:carbamazepine ratio increased 3—4 fold. After discontinuation of quetiapine or substitution of oxcarbazepine for carbamazepine, CBZ-E and carbamazepine levels returned to baseline. The mechanism of this interaction may be inhibition of epoxide hydrolase and/or CBZ-diol glucuronidation by quetiapine. CBZ-E is known to have neurotoxic properties; one patient receiving quetiapine concurrently with carbamazepine experienced ataxia and agitation. The clinician should consider monitoring CBZ-E levels if quetiapine is added to carbamazepine therapy.[4084]

Multiple daily doses of cimetidine [6445] (400 mg three times a day for 4 days) resulted in a 20% decrease in quetiapine clearance. Although it is not usually necessary to adjust the dose of quetiapine when cimetidine is coadministered, patients should be monitored for a potential increase in the pharmacologic effects of quetiapine.

Erythromycin is an inhibitor of CYP3A4, which is involved in the metabolism of quetiapine.[4978] [6458] Co-administration of erythromycin and quetiapine resulted in decreased clearance of quetiapine, increased quetiapine plasma concentrations, and prolonged half-life. Nineteen patients received quetiapine 200 mg PO twice a day for roughly 7 days. The quetiapine was then combined with erythromycin 500 mg PO 3 times a day for 5 days. Mean quetiapine AUC increased 129% (range 15—300%) and the half-life was elevated from 7 to 16 hours. Pharmacokinetic changes of this magnitude will most likely increase the incidence of adverse events, such as drowsiness, orthostatic hypotension, xerostomia, and dizziness.[8115] Clarithromycin is likely to have similar effects on quetiapine metabolism. Macrolides that do not inhibit CYP3A4, such as azithromycin and dirithromycin, should be considered in patients taking quetiapine.

The cytochrome P450 3A4 (CYP3A4) isoenzyme is involved in the metabolism of quetiapine.[6458] Ketoconazole, a significant inhibitor of CYP3A4, reduced the oral clearance of quetiapine by 84% resulting in a 335% increase in quetiapine maximum plasma concentrations.[4234] [5855] Fluconazole, itraconazole, and voriconazole may also increase plasma concentrations of quetiapine through CYP3A4 inhibition.[4718] Although data are not available from clinical trials, caution is advised when quetiapine is administered with other potent CYP3A4 enzyme inhibitors such as anti-retroviral protease inhibitors [4718], delavirdine [4718], efavirenz (substrate and an inducer) [4718], imatinib, STI-571 [4718], and troleandomycin [4718]. Examples of other significant inhibitors of CYP3A4 include: aprepitant (minor) [7438], dalfopristin; quinupristin; danazol [4718], diltiazem [4718], nicardipine (minor) [4718], verapamil [4718], and zafirlukast [4718]. This list is not inclusive of all CYP3A4 inhibitors. Although fluoxetine is reported to have some CYP3A4 inhibitory activity, fluoxetine co-administration did not alter the pharmacokinetics of quetiapine in one study reported by the manufacturer of quetiapine.[5855]

Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa, pergolide, pramipexole, or ropinirole therapy by blocking dopamine receptors in the brain. Quetiapine may also cause additive sedation with drugs like entacapone [5574], pramipexole [5640], ropinirole [8018] and tolcapone [5578]. In general, however, atypical antipsychotics like quetiapine are less likely to interfere with these therapies than traditional antipsychotic agents.

The prolactin-lowering effect of bromocriptine or cabergoline may be antagonized by medications that increase prolactin levels such as the antipsychotic drugs. In addition, bromocriptine and cabergoline, which are dopamine agonists, may diminish the effectiveness of dopamine antagonists such as the antipsychotics. In general, however, atypical antipsychotics like quetiapine are less likely to interfere with these therapies than traditional antipsychotic agents.[5066] [4680] [6459]

Quetiapine decreases lorazepam clearance by about 20%.[5855] Patients should be monitored for a potential increase in the pharmacologic effect of lorazepam when coadministered with quetiapine. Somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with other anxiolytics, sedatives, and hypnotics [5855], opiate agonists, buprenorphine, butorphanol, dronabinol, THC, nalbuphine, pentazocine, or other CNS depressants may result in additive sedative effects.[5855]

Ethanol should be avoided in patients taking quetiapine due to the potential for additive CNS effects.[5855]

In addition to additive CNS depressant effects, quetiapine may potentially increase the risk of seizures when given concurrently with tramadol.[5043]

In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone (GnRH) analogs (cetrorelix, ganirelix, goserelin, leuprolide, or triptorelin) since hyperprolactinemia downregulates the number of pituitary GnRH receptors. Quetiapine has a lower incidence of hyperprolactinemia, however, versus typical antipsychotics.[6813]

The mean maximum concentration and extent of absorption of total and free valproic acid at steady state was decreased by 10 to 12% when divalproex (500 mg bid) was administered with quetiapine (150 mg twice daily). The mean oral clearance of total valproic acid (administered as divalproex 500 mg bid) was increased by 11% in the presence of quetiapine (150 mg twice daily). The changes were not significant.[5855] Pharmacodynamically, the combined use of valproic acid, divalproex sodium and quetiapine could lead to increased sedation.

In a published case, it has been hypothesized that the combination of lovastatin and quetiapine resulted in prolongation of the QTc interval. The suggested mechanism is competitive inhibition of the CYP3A4 isoenzyme leading to elevated quetiapine plasma concentrations. Both lovastatin and quetiapine are CYP3A4 substrates. The QTc interval returned to baseline when the lovastatin dose was reduced. The clinical significance and reproducibility of this interaction is unknown.[6460]

Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents.[7018] Antipsychotics should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.[5442] [5698]

The atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.[7335] While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.[7238] Patients taking antidiabetic agents should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.

Interactions last revised 9/1/2005 9:31:00 PM

Adverse Reactions

• abdominal pain	• neuroleptic malignant syndrome
• asthenia	• orthostatic hypotension
• constipation	• polydipsia
• diabetes mellitus	• polyuria
• dizziness	• priapism
• drowsiness	• rhinitis
• dyspepsia	• seizures
• dysphagia	• sinus tachycardia
• elevated hepatic enzymes	• syncope
• hyperglycemia	• tardive dyskinesia
• hypotension	• weakness
• hypothyroidism	• weight gain
• maculopapular rash	• xerostomia

Neuroleptic malignant syndrome (NMS) has been associated with administration of antipsychotic drugs. Two possible cases of NMS (0.1% of patients) were reported during initial clinical trials with quetiapine. NMS is characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Increased serum creatine phosphokinase (CPK), rhabdomyolysis, and acute renal failure also have occurred. NMS does not appear to be dose-related. Experience with other neuroleptic agents suggests that several predisposing factors may contribute to the development of NMS including heat stress, physical exhaustion, dehydration, and organic brain disease. Quetiapine should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered.

Tardive dyskinesia (TD), a potentially irreversible syndrome characterized by involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Involuntary orofacial movements (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities may occur. TD is observed more frequently in elderly women. It is believed that the likelihood of developing TD increases with prolonged treatment and cumulative doses; however, it can also develop, although less commonly, after short periods of time and with low dosages. The incidence of TD with use of quetiapine is unknown; however, it is believed that this drug has a low propensity for producing TD because it does not appear to produce D2 supersensitivity in the striatal region of the brain. Nevertheless, in patients who require chronic treatment with quetiapine, the lowest possible dose and the shortest duration of treatment should be used. Patients should be monitored routinely (at 3—6 month intervals) for movement disorders. If signs or symptoms of TD develop, discontinuation of quetiapine therapy should be considered.

During initial placebo-controlled trials, there were no differences between quetiapine and placebo treatment groups in the incidence of extrapyramidal symptoms (e.g., akathisia, cogwheel rigidity, tremor, hypokinesia). This may be explained in part by the greater affinity of this drug for 5-HT2 receptors relative to D2 receptors, as well as the selectivity of quetiapine for dopamine receptors on mesolimbic rather than nigrostriatal neurons. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study evaluated the effectiveness of selected atypical antipsychotics (olanzapine, quetiapine, risperidone, ziprasidone) and perphenazine in schizophrenic patients (see Atypical Antipsychotic Overview). In the secondary evaluation of adverse events and reasons for drug discontinuation, the rate of occurrence of any serious adverse effect was similar among groups.[8303] However, the discontinuation of treatment due to extrapyramidal symptoms (EPS) was low in the risperidone group (3%; 11/341) vs. the perphenazine group (8%; 22/261).[8303] Olanzapine, quetiapine, and ziprasidone also had low incidences of EPS (2—4%).

Quetiapine can cause orthostatic hypotension associated with dizziness, tachycardia, and in rare cases, syncope. Orthostatic hypotension occurred in about 10% of patients during initial clinical trials and syncope was reported in 1% of patients. Orthostatic hypotension is most likely to occur during the initial dosage titration period and is thought to be caused by alpha1-adrenergic blockade, resulting in peripheral vasodilation. Conditions that may predispose patients to hypotension, such as hypovolemia and dehydration, should be corrected, if possible, before starting therapy (see Precautions). The risk of orthostatic hypotension can be minimized by limiting the initial dose of quetiapine to 25 mg PO twice daily.

The most frequent adverse events associated with use of quetiapine are mild weight gain (23%), drowsiness (18%), dizziness (10%), constipation (9%), orthostatic hypotension (7%), xerostomia (7%), and dyspepsia (6%). Adverse events that most often resulted in discontinuation of quetiapine were drowsiness (0.8% discontinuation rate) and hypotension (0.4% discontinuation rate). Other adverse effects that occurred in more than 2% of patients and were reported more frequently in quetiapine-treated patients than in placebo-treated patients were sinus tachycardia (7%), asthenia (4%), maculopapular rash (4%), abdominal pain (3%), and rhinitis (3%). Abdominal pain, dyspepsia, and weight gain appear to be dose related. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial, quetiapine was associated with highest rate (31%) of anticholinergic adverse effects (urinary hesitancy, dry mouth, constipation) compared to other atypical antipsychotics and perphenazine (range 20—25%).[8303]

During initial clinical trials, seizures occurred in 0.8% of patients treated with quetiapine compared with 0.5% of patients treated with placebo. As with other antipsychotic drugs, quetiapine should be used with caution in patients with a history of a seizure disorder or with conditions or drugs that may lower the seizure threshold.

Patients should be monitored for signs and/or symptoms of hypothyroidism during treatment with quetiapine, since use of this drug has been associated with dose-dependent decreases in total and free thyroxine (T4). Although most of these changes were not clinically significant, 0.4% of patients experienced clinically relevant increases in TSH.

Quetiapine has been associated with elevated hepatic enzymes (primarily AST) that are transient and reversible. Increases in hepatic enzymes to >= 3 times the upper limit of normal occurred in 6% of quetiapine-treated patients compared with 1% of placebo-treated patients. Elevations of hepatic enzymes usually occurred within the first three weeks of therapy.

Hyperglycemia has been occasionally reported during quetiapine therapy, even in patients with no prior history of hyperglycemia. While causal relationships and incidence have not been determined, temporal associations of quetiapine therapy with the precipitation or aggravation of diabetes have been reported. Atypical antipsychotics may have effects on glucose metabolism that are independent of their effect on weight gain; one study noted that patients taking atypical agents (e.g., clozapine, olanzapine, quetiapine) were 9% more likely to have a new diagnosis of diabetes mellitus than patients taking older therapies.[3917] The possibility of impaired glucose tolerance should be considered in patients receiving quetiapine who develop symptoms of hyperglycemia or diabetes, such as polydipsia, polyuria, polyphagia, and weakness. In patients with severe treatment-emergent hyperglycemia, discontinuation of therapy should be considered. Elevations in triglyceride levels may also occur. In placebo-controlled trials, quetiapine-treated patients had increases in baseline cholesterol and triglyceride concentrations of 11% and 17%, respectively, compared with a slight decrease in placebo-treated patients. A well supported case (temporal association, positive dechallege) of Type 2 diabetes mellitus occurring in a patient shortly after initiation of quetiapine for bipolar disorder has been reported. Measured blood glucose reached a peak of 600 mg/dl. The patient had risk factors that predisposed her to development of diabetes (e.g., obesity, hyperlipidemia). The authors suspects that the diabetes onset was not due to antipsychotic-induced weight gain, as her weight was relatively stable during quetiapine treatment. Ziprasidone therapy was successfully instituted without return of diabetes.[7418]

One case of priapism has been reported in a patient treated with quetiapine. While a causal relationship has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism and it is possible that quetiapine may also have this potential.

Aspiration and esophageal dysmotility resulting in dysphagia have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients. Quetiapine and other antipsychotic drugs should be used with caution in patients as increased risk for aspiration pneumonia.

Adverse Reactions last revised 10/10/2005 6:05:00 PM

Monitoring Parameters

Monitoring Parameters
•AIMS assessment
•blood glucose
•LFTs
•neurologic function
•ophthalmologic exam
•serum cholesterol profile
•weight

Product Information

More information about the following products is available:
• Seroquel®

Patient Education

Quetiapine tablets

What are quetiapine tablets?
QUETIAPINE (Seroquel®) helps to treat schizophrenia or bipolar disorder, also known as manic-depression. Quetiapine can help you to keep in touch with reality, stabilize the mood, and reduce your mental problems. Generic quetiapine tablets are not yet available.

What should my health care professional know before I take quetiapine?
They need to know if you have any of these conditions:
•an alcohol abuse problem
•brain tumor or head injury
•breast cancer
•cataracts
•diabetes (increased blood sugar) or a family history of diabetes
•difficulty swallowing
•heart disease
•kidney disease
•liver disease
•low blood pressure (hypotension) or dizziness when standing up
•Parkinson's disease
•previous heart attack
•seizures (convulsions)
•thyroid problems
•an unusual or allergic reaction to quetiapine, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I take this medicine?
Take quetiapine tablets by mouth with or without food. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If quetiapine upsets your stomach you can take it with food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your prescriber's advice.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

Patients over age 65 years may have a stronger reaction to this medicine and need smaller doses.

What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What drug(s) may interact with quetiapine?
•alcohol
•antifungal medicines, such as fluconazole, itraconazole, ketoconazole, or voriconazole
•barbiturates
•carbamazepine
•cimetidine
•erythromycin
•levodopa
•lorazepam
•medicines for diabetes
•medicines for mental problems and psychotic disturbances
•oxcarbazepine
•phenobarbital
•phenytoin
•rifampin
•thioridazine

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What side effects may I notice from taking quetiapine?
Side effects that you should report to your prescriber or health care professional as soon as possible:
Rare or uncommon:
•difficulty swallowing
•severe weakness
•fainting spells
•inability to control muscle movements in the face, hands, arms, or legs
•increased thirst or hunger
•increased need to pass urine
•loss of balance or difficulty walking
•restlessness or need to keep moving
•seizures
•skin rash
•stiff muscles
•sexual difficulties
More common:
•dizziness or lightheadedness
•fast or irregular heartbeat (palpitations)

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
•constipation
•drowsiness or dizziness
•dry mouth
•nausea
•runny nose
•stomach pain
•unusual tiredness
•weight gain

What should I watch for while taking quetiapine?
Visit your prescriber or health care professional for regular checks on your progress. It may be several weeks before you see the full effects of quetiapine. Do not suddenly stop taking quetiapine. You may need to gradually reduce the dose. Only stop taking quetiapine on your prescriber's advice.

Your health care provider may suggest that you have your eyes examined prior to starting quetiapine, and every 6 months thereafter.

You may get dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how quetiapine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase dizziness and drowsiness. Avoid alcoholic drinks.

If you notice an increased hunger or thirst, different from your normal hunger or thirst, or if you find that you must frequently use the restroom (excessive urination), you should contact your health care provider as soon as possible. You may need to have your blood sugar monitored.

Do not treat yourself for colds, diarrhea or allergies. Ask your prescriber or health care professional for advice, some nonprescription medicines may increase possible side effects.

If you are going to have surgery tell your prescriber or health care professional that you are taking quetiapine.

Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 20 degrees and 25 degrees C (68 degrees and 77 degrees F). Throw away any unused medicine after the expiration date.

[Revised: 12/28/2004]

Acetaminophen; Tramadol
Ultracet®

Classification:
• Analgesics

Description, Mechanism of Action, Pharmacokinetics

NOTE: This monograph discusses the use of the acetaminophen; tramadol combination product for the management of pain. Clinicians may wish to consult the individual drug monographs for more information about each agent.

Description: Acetaminophen; tramadol is used orally for short-term (<= 5 days) management of acute pain. Acetaminophen is a non-narcotic analgesic and tramadol is a centrally acting analgesic with a unique, dual mechanism of action. Some studies have evaluated acetaminophen; tramadol for the treatment of chronic pain, such as osteoarthritis and low-back pain. In a 4-week study, pain relief scrores between acetaminophen; tramadol and acetaminophen; codeine were similar.[3346] The primary advantage of Ultracet® appears to be a quicker onset of action than Ultram® and greater pain relief than either acetaminophen or tramadol given alone. However, in oral surgical patients the analgesia produced by acetaminophen; tramadol was comparable to ibuprofen. Ultracet® was approved by the FDA August 15, 2001.

Mechanism of Action: Acetaminophen; tramadol produces analgesia via two different mechanisms of action leading to a synergistic analgesic effect.
•Acetaminophen: Acetaminophen acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects.
•Tramadol: Tramadol appears to have two complementary mechanisms of pain relief, specifically binding of the parent drug and M1 metabolite to µ-opioid receptors and reuptake inhibition of serotonin and norepinephrine. The affinity of the parent drug for µ-opioid receptors is much less than the M1 metabolite, with the M1 metabolite being 6 times more potent in analgesic effects and 200 times more potent in µ-binding activity.

The reuptake inhibition of serotonin and norepinephrine may lead to reduced spinal cord pain transmission. The stereochemistry of tramadol influences the affinity of these compounds to various receptors. The (+) enantiomer has higher affinity for the µ-receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha2-adrenergic receptors.[897] The racemate of the trans isomer of tramadol is more potent than either enantiomer alone. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100—1000 times less than imipramine.

Pharmacokinetics: Acetaminophen; tramadol combination product is administered orally.
•Acetaminophen: Acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations of acetaminophen from the combination product occur in one hour. Absorption, which occurs primarily from the small intestine, may be decreased if taken with a high-carbohydrate meal. Protein binding is minimal. Acetaminophen is metabolized in the liver via glucuronidation and sulfate conjugation and is excreted in the urine as glutathione and sulfate conjugates. However about 10—15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 and 1A2 and then glucuronidation to cysteine and mercapturic acid conjugates. In cases of glucuronide depletion, such as acetaminophen overdose, a hepatotoxic metabolite is formed. The mean half-life of acetaminophen as part of the combination product is 2.5 hours. The pharmacokinetics of acetaminophen are not altered when combined with tramadol.
•Tramadol: Racemic tramadol and the M1 metabolite reach peak plasma concentrations at 2 and 3 hours, respectively, following oral administration. Absolute bioavailability of tramadol from the combination product has not been determined, but bioavailability of tramadol as a single product is roughly 75%. When acetaminophen; tramadol was administered with food, the time to peak concentrations was delayed, but the extent of absorption and final peak concentrations were not affected. For oral surgical patients, the onset of analgesia for the combination product occurred in less than one hour, more quickly than individual tramadol. Minimal protein binding occurs (roughly 20%). Tramadol crosses the placenta and about 0.1% is distributed into breast milk. Tramadol undergoes significant first-pass metabolism. The major metabolic pathways appear to be N- and O- demethylation, glucuronidation and sulfation. Extensive hepatic metabolism occurs via isoenzymes CYP2D6 and CYP3A4. The formation of the active metabolite M1 (O-desmethyltramadol) is dependent upon the 2D6 enzyme and therefore inhibition of this enzyme can affect therapeutic response (see Drug Interactions). The elimination mean half-life of the racemic tramadol and M1 metabolite is 5 and 7 hours, respectively. Multiple dosing lengthens the half-life of racemic tramadol to 7—9 hours. About 90% of a dose is excreted in the urine (30% as unchanged drug and 60% as metabolites) and 10% is excreted in the feces.

•Special Populations: In clinical trials, tramadol clearance was 20% higher in females versus males; the clinical significance of this effect is not known. Approximately 7% of the general population are termed "poor metabolizers" of tramadol due to reduced activity of the CYP2D6 isoenzymes. Phase 1 pharmacokinetic studies have shown "poor metabolizers" have 20% higher concentrations of tramadol and 40% lower concentrations of the active M1 metabolite. The addition of drugs that inhibit CYP2D6 to these patients' regimens could further alter tramadol concentrations; the clinical significance of these actions is not known.

The pharmacokinetics of acetaminophen; tramadol have not been studied in patients with renal or hepatic impairment. In patients with a creatinine clearance < 80 ml/min, the half-life of tramadol increases 1.5—2 times as compared to patients with normal renal function. Less than 7% of tramadol and M1 are removed by dialysis during a 4 hour session. In patients with cirrhosis or significant liver dysfunction, the half life of tramadol and M1 increases 2—3 times as compared to normal. The half-life of acetaminophen also increases with hepatic impairment. The use of acetaminophen; tramadol is not recommended in hepatic dysfunction.

Description, Mechanism of Action, Pharmacokinetics last revised 11/6/2003 5:22:00 PM

Indications

• arthralgia†	• moderate pain
• bone pain†	• myalgia†
• dental pain†	• osteoarthritis†
• headache†

† non-FDA-approved indication

Dosage

For the short term (5 days or less) treatment of acute moderate pain including arthralgia†, headache†, myalgia†, osteoarthritis†, dental pain† following oral surgery or chronic conditions such as low-back pain†, bone pain† and cancer-related pain†:
Oral dosage:
Adults, the elderly and adolescents >= 16 years: 2 tablets (37.5 mg tramadol and 325 mg acetaminophen per tablet) PO every 4—6 hours as needed, not to exceed 8 tablets/24 hours. Cautious dosage selection in the elderly is recommended.
Adolescents and children < 16 years: Safe and effective use has not been established.

Maximum Dosage Limits:
•Adults: 300 mg/day PO tramadol and 2600 mg/day PO acetaminophen.
•Elderly: 300 mg/day PO tramadol and 2600 mg/day PO acetaminophen.
•Adolescents >= 16 years: 300 mg/day PO tramadol and 2600 mg/day PO acetaminophen.
•Adolescents < 16 years: Safe and effective use has not been established.
•Children: Safe and effective use has not been established.

Patients with hepatic impairment:
Use in patients with hepatic impairment is not recommended.

Patients with renal impairment:
The following guidelines are for adults and adolescents >= 16 years.
CrCl >= 30 ml/min: No dosage adjustment needed.
CrCl < 30 ml/min: No more than 2 tablets of Ultracet® PO every 12 hours.

Intermittent hemodialysis:
See dosage for CrCl < 30 ml/min. Hemodialysis removes < 7% of a dose of tramadol; supplemental dosing of acetaminophen is not required following hemodialysis. It is unlikely that supplemental dosing with Ultracet® is required following dialysis.

Indications...Dosage last revised 7/1/2002

Administration Guidelines

NOTE: This monograph discusses the use of the acetaminophen; tramadol combination product for the management of pain. Clinicians may wish to consult the individual monographs for more information about the specific dosing of each agent.

Oral Administration
•Tramadol is administered with or without food.
•Slower titration of tramadol to the effective analgesic dose may decrease the incidence of nausea and vomiting.

Administration last revised 7/1/2002

Contraindications/Precautions

• abrupt discontinuation	• hepatitis
• acetaminophen hypersensitivity	• immunosuppression
• ethanol intoxication	• increased intracranial pressure
• opiate agonist hypersensitivity	• infection
• alcoholism	• labor
• anemia	• neutropenia
• asthma	• obstetric delivery
• bone marrow suppression	• pregnancy
• breast-feeding	• renal failure
• children	• renal impairment
• driving or operating machinery	• respiratory depression
• elderly	• salicylate hypersensitivity
• G6PD deficiency	• seizure disorder
• GI disease	• seizures
• head trauma	• substance abuse
• hepatic disease

• Absolute contraindications are in italics.

Acetaminophen; tramadol combinations should not be used in a patient with a known acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Patients who have demonstrated a prior opiate agonist hypersensitivity reaction to codeine or other opiate agonists should not receive tramadol because there is an increased risk of developing anaphylactoid reactions to tramadol. Postmarketing surveillance has revealed reports of anaphylactoid reactions following the initial tramadol dose, particularly in patients with a history of codeine hypersensitivity. Any patient who is hypersensitive to tramadol, acetaminophen or any of the components in the commercial formulation should not receive acetaminophen; tramadol.

Normal and excessive doses of tramadol have been associated with seizure activity. Additionally, tramadol should be used with caution in patients who are at risk of seizures including those who have a pre-existing seizure disorder, are receiving medications which reduce the seizure threshold (see Drug Interactions), who have certain medical conditions (i.e., increased intracranial pressure, CNS infection, head trauma), or who are experiencing ethanol or illicit drug withdrawal. In tramadol overdose, naloxone administration may increase the risk of seizure. In addition, administration of tramadol to patients with increased intracranial pressure or head trauma may obscure the existence, extent, or course of intracranial pathology because tramadol induces pupillary changes (miosis).

Acetaminophen; tramadol is contraindicated for use in patients with hepatic disease, hepatitis or alcoholism as both agents are extensively metabolized in the liver. The use of acetaminophen; tramadol is contraindicated in cases of acute ethanol intoxication and intoxication with other agents such as opiate agonists, hypnotics, centrally acting analgesics, or psychotropic drugs. Acetaminophen; tramadol should not be used with alcohol. Alcoholic patients are at risk for acetaminophen-induced hepatotoxicity as well as increased seizure activity with tramadol (see Adverse Reactions). Acetaminophen-induced hepatotoxicity should be suspected in alcoholic patients with aminotransferase levels > 1000 U/L and acetaminophen blood levels should be checked in these patients. Patients using acetaminophen; tramadol should be warned not to consume additional OTC acetaminophen or prescription tramadol due to the potential for overdose.

Acetaminophen should be used cautiously in patients with asthma who also have salicylate hypersensitivity. Of 50 patients with aspirin-sensitive asthma, 17 had either a naso-ocular or bronchospastic reaction after ingestion of either 1000 mg or 1500 mg of acetaminophen. The magnitude of FEV1 decline after a mean aspirin dose of 47 mg was similar to the decline seen after a mean acetaminophen dose of 1227 mg. The lower the aspirin provocative dose, the more likely patients were to cross-react to acetaminophen. For example, 5 of 6 patients with aspirin-induced bronchospasm after a dose of 30 mg or less had cross-reactivity to acetaminophen whereas no patients had cross-reactivity when the provocative aspirin dose was at least 150 mg. The acetaminophen challenges were performed before any aspirin challenges and all patients had a measured FEV1 of at least 70% of predicted or best previously recorded value, an absolute value greater than 1.5 liters, and a fall of less than 15% in FEV1 from morning baseline during placebo challenges.[1112]

Administer acetaminophen; tramadol with caution to patients at risk for respiratory depression. Alternative non-opioid analgesics should be considered. Respiratory depression is possible with large doses of tramadol, especially when given concurrently with ethanol, anesthetic agents or other respiratory depressants. If respiratory depression occurs, treat as an overdose; however, administer naloxone cautiously in these situations due to an increased risk of seizures.

Tramadol should be used with caution in patients with GI disease. It may be difficult to assess the condition of patients with acute abdominal conditions if they are taking tramadol.

Acetaminophen; tramadol should not be used in patients with a current or previous opioid substance abuse problem. The risk for dependence is not limited to patients with a previous opioid abuse history. Tramadol has been shown to reinitiate physical dependence in some patients. Patients who have recently taken substantial amounts of opiate agonists may experience withdrawal symptoms after treatment with tramadol. Psychologic dependence similar to that of codeine or dextropropoxyphene is possible with tramadol.

To prevent withdrawal symptoms, avoid abrupt discontinuation of tramadol. Withdrawal symptoms may include anxiety, sweating, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, panic attacks, severe anxiety, paresthesias, and hallucinations (rarely). Clinical experience suggests that withdrawal symptoms may be relieved by tapering the dosage of tramadol.

Tramadol should be administered with caution to patients with renal impairment or renal failure. Impaired renal function affects the rate and extent of excretion for both tramadol and its active metabolite M1. Dosage reductions are recommended if creatinine clearance falls below 30 ml/min (see Dosage). It may take several days for elevated plasma concentrations and toxicity to develop.

Acetaminophen; tramadol is classified as FDA pregnancy risk category C. Studies have not assessed tramadol use during human pregnancy; it should only be given if the need clearly outweighs the risk. Tramadol crosses the placenta and the effects on postnatal growth, development and functional maturation of the fetus are unknown. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported with chronic use of tramadol during pregnancy. High dosage levels in animal studies show tramadol as embryotoxic and fetotoxic but not teratogenic. Tramadol should not be given to women prior to labor, or during obstetric delivery unless the benefits outweigh the risk. Tramadol has been used outside the U.S. for the management of pain associated with labor. The effect of tramadol on respiratory depression in the neonate has been studied and was not significantly different from that following the administration of morphine or meperidine.[902] No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women.[4441] Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 infants exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.

Tramadol and its metabolites are excreted into human milk in small amounts. Acetaminophen also crosses into breast milk, with a concentration ranging from 0.1—1.85% of the maternal dose. According to the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding.[4201] The AAP regards acetaminophen as a maternal medicine that is usually compatible with breast-feeding. No recommendations are available from AAP for tramadol. Because of the potential for serious adverse reactions in breast-fed infants, including respiratory depression, alternative analgesics to acetaminophen; tramadol should be considered for a woman who is breast-feeding her infant.

In studies looking at the single agent tramadol, elderly patients > 75 years experienced slightly elevated serum concentrations and a prolonged elimination half-life. In elderly patients >= 65 years of age, the pharmacokinetics of acetaminophen; tramadol were not altered. In general, elderly patients will vary in their tolerance of acetaminophen; tramadol. Although specific guidelines are not available, a lower starting dose, slower dose titration, and a lower maximum daily dose may be prudent in these patients.

In the US, the safety and efficacy of tramadol in children < 16 years of age have not been established. Acetaminophen in appropriate dosages is safe for use in children. The manufacturers of acetaminophen; tramadol recommend that it only be used in adult patients.

Patients should be warned against driving or operating machinery until they know how acetaminophen; tramadol may affect them. Tramadol may affect the ability to safely perform hazardous tasks.

Overdose with acetaminophen may lead to hepatic necrosis, hepatic failure and death. Emergency help should be sought immediately for suspected acetaminophen overdose. Patients with G6PD deficiency who overdose with acetaminophen may be at increased risk for drug-induced hemolysis. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.

Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen in patients with bone marrow suppression, especially neutropenia or immunosuppression.

Acetaminophen may interfere with some home blood glucose monitoring systems resulting in decreases of > 20% in mean glucose values. This effect seems to be drug, concentration and system dependent.

Contraindications last revised 7/23/2004 3:39:00 PM

Drug Interactions

• Acetaminophen			Opiate agonists
• Amiodarone		• Oxcarbazepine
• Amitriptyline		• Paroxetine
• Amoxapine			Phenothiazines
	Anxiolytics, Sedatives, and Hypnotics	• Phenytoin
	Barbiturates	• Pimozide
• Bupropion		• Pramipexole
• Busulfan		• Prilocaine
• Carbamazepine		• Procarbazine
• Chloroquine		• Propafenone
• Clozapine		• Propoxyphene
• Cocaine		• Quetiapine
• Cyclobenzaprine		• Quinacrine
• Diflunisal		• Quinidine
• Digoxin		• Quinine
• Dronabinol, THC		• Rifabutin
• Droperidol		• Rifampin
• Entacapone		• Rifapentine
• Ethanol		• Risperidone
• Ethotoin		• Ritonavir
• Fosphenytoin		• Ropinirole
• Furazolidone			Salicylates
• Gefitinib			Sedating H1-blockers
	General Anesthetics		Selective serotonin reuptake inhibitors (SSRIs)
• Haloperidol			Serotonin norepinephrine reuptake inhibitors
• Imatinib, STI-571			Skeletal Muscle Relaxants
• Isoniazid, INH		• St. John's Wort, Hypericum perforatum
• Linezolid		• Sulfinpyrazone
• Maprotiline		• Terbinafine
• Meperidine		• tobacco
• Mirtazapine		• Tolcapone
	Mixed opiate agonists/antagonists	• Trazodone
• Molindone			Tricyclic antidepressants
	Monoamine oxidase inhibitors (MAOIs)	• Valerian, Valeriana officinalis
• Naloxone		• Warfarin
• Nefazodone		• Zidovudine, ZDV
• Olanzapine

NOTE: This monograph discusses the use of this combination product for the management of pain. Clinicians may wish to consult the individual monographs for more information about the specific drug interactions of each agent.

Many prescription and non-prescription medicines contain acetaminophen. High dosages of acetaminophen on a chronic basis can cause depletion of glutathione stores, which can lead to a greater production of the hepatotoxic metabolite, NAPQI.[4925] To limit the hepatotoxic risk of acetaminophen overdosage, avoid concurrent use of products that contain acetaminophen, as the maximum daily dose (i.e., 4 g/day for adults) may be exceeded. Advise patients to carefully read the ingredients of any OTC or prescription products, or to ask their health care provider if they are not sure.[4925]

Enzyme-inducing anticonvulsant agents, such as carbamazepine, oxcarbazepine, barbiturates (e.g., phenobarbital, primidone), ethotoin, phenytoin, or fosphenytoin may induce cytochrome P450 isoenzymes.[4718] The analgesic activity of acetaminophen and tramadol may be reduced.[5043] Anticonvulsants may augment CNS depression seen with tramadol, and tramadol and may decrease the seizure threshold and thus, interfere with the ability of anticonvulsants to control seizures.[4754] Also, an increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1000 mg daily and phenobarbital 100 mg daily [107] and with acetaminophen 1300—6200 mg daily and phenytoin. In both cases, acetaminophen cessation led to serum transaminase normalization within 2 weeks.[107] [4927] A reduced dose of acetaminophen; tramadol is recommended when used in patients without epilepsy who are receiving barbiturates, due to additive CNS depression. Concomitant usage of tramadol and carbamazepine is not recommended.

As cytochrome P450 isoenzyme inducers, rifampin, rifapentine, or rifabutin could induce the metabolism of acetaminophen; tramadol, altering the clinical response. For example, the analgesic activity of acetaminophen may be reduced. Also, an increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI.[4718] Hepatic failure and encephalopathy has been attributed to the combination of rifampin and acetaminophen. A 32 year-old female with normal prothrombin time and liver function developed a serum alanine transaminase concentration of 450 IU, an international normalized ratio of 5.2, confusion, and agitation 2 days after starting rifampicin 600 mg twice daily. She had been taking 2—4 grams of acetaminophen on a daily basis for several weeks. Her liver dysfunction resolved with rifampicin and acetaminophen withdrawal and vitamin K and N-acetylcysteine administration.[4929]

The combination of isoniazid, INH and acetaminophen has caused severe hepatotoxicity.[4930] [4931] Isoniazid, while present in the body, induces the hepatic cytochrome P450 isoenzyme 2E1.[3733] In slow N-acetylators, induction of 2E1 occurs for about 2 weeks after INH clearance by the body. Induction of 2E1 activity may potentially increase the risk for acetaminophen-induced hepatotoxicity via enhanced generation of acetaminophen's hepatotoxic metabolite, NAPQI.[3733] Concomitant use of INH and acetaminophen when given at the same time resulted in a markedly decreased formation clearance for NAPQI in patients who received INH daily for 6 months. However, decreased formation clearance for NAPQI only persisted in slow acetylators when acetaminophen was administered 12 hours after INH administration. Rapid acetylators had enhanced formation of NAPQI.[4932] Thus, the timing of acetaminophen administration and whether a person is a fast or slow acetylator appears to affect the likelihood of acetaminophen hepatotoxicity..

As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect the analgesic effect of tramadol (see Mechanism of Action). Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor (see Pharmacokinetics).[5043] Agents that inhibit CPY2D6 include amiodarone [4718], chloroquine[4718], haloperidol [4718], imatinib, STI-571 [4718], gefitinib [5012], ritonavir [4718], terbinafine [4718], propoxyphene [4718], quinacrine [4718], quinine [4718], quinidine [4718], and propafenone [4718]. The list of drugs that inhibit CYP2D6 is not all inclusive. Reduced analgesic effects of tramadol are possible when a concurrent CYP2D6 inhibitor is used.

Administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold. Tricyclic antidepressants and other tricyclic compounds (e.g., cyclobenzaprine) that decrease the seizure threshold have been associated with increased risk of seizures when given concurrently with tramadol.[2543] Other agents that may decrease the seizure threshold include neuroleptics (e.g., phenothiazines), amoxapine, maprotiline, bupropion, clozapine, meperidine, and cocaine. Additive CNS depression and respiratory depression may also occur when some of these agents are given concurrently with acetaminophen; tramadol.[5043] A reduced dose of acetaminophen; tramadol is recommended when used in patients who take a phenothiazine. Also, as the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by amitriptyline or bupropion may affect the analgesic effect of tramadol (see Mechanism of Action).[4718] Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor (see Pharmacokinetics).[5043]

Use acetaminophen; tramadol extremely cautiously, if at all, in patients also receiving monoamine oxidase inhibitors (MAOIs), including drugs with MAOI activity (e.g., furazolidone, linezolid and procarbazine). Concomitant usage of acetaminophen; tramadol and MAOIs is associated with an increased risk of seizures or serotonin syndrome.[5043] International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy.

Tramadol may cause additive CNS and/or respiratory depression when used with other agents that produce these effects, such as opiate agonists. Concomitant use of tramadol and other opiate agonists may increase the risk of seizures; avoid concurrent use whenever possible.[5043] If co-administered, use extreme caution; a reduced acetaminophen; tramadol dose is recommended.

Acetaminophen; tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants. A reduced dose of acetaminophen; tramadol is recommended when used in patients who use general anesthetics or anxiolytics, sedatives, and hypnotics. Other agents that may contribute to CNS depression when used with tramadol include mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine), droperidol, dronabinol, THC, entacapone, sedating H1-blockers, molindone, olanzapine, quetiapine, pimozide, risperidone, pramipexole, ropinirole, skeletal muscle relaxants, trazodone, and tolcapone. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of tramadol.[4718] Close monitoring for side effects in patients receiving tramadol-containing products and chlorpheniramine or diphenhydramine is recommended. Extreme caution is needed during concomitant use of any CNS-depressant drugs and acetaminophen; tramadol.

The risk of seizures and serotonin syndrome may be enhanced by concurrent use of tramadol and selective serotonin reuptake inhibitors(SSRIs).[5043] Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures.[2543] Several cases of serotonin syndrome have been reported following the administration of tramadol with a SSRI.[5933] [6683] [6684] Citalopram [4718], escitalopram [4718], fluoxetine [5043], paroxetine [5043], and sertraline [4718] inhibit the formation of the active M1 metabolite of tramadol by inhibiting cytochrome P450 2D6. The inhibition of M1 formation may decrease the analgesic effectiveness of tramadol but increase the serum concentration of the parent compound (see Mechanism of Action).

Medications that decrease the reuptake of serotonin, such as serotonin norepinephrine reuptake inhibitors (e.g., duloxetine or venlafaxine), or nefazodone may cause serotonin syndrome in patients taking tramadol.[5043] Also, additive CNS depression may occur when tramadol is used with a mirtazapine or nefazodone. The addition of tramadol to extended-release venlafaxine 300 mg/day and mirtazapine 30 mg/day likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful.[6687]

Medications that decrease the reuptake of serotonin, such as St. John's wort, Hypericum perforatum, may cause serotonin syndrome in patients taking tramadol.[5043] Also about 10—15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 (major pathway), 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).[2678] Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.[4935]

The risk of developing hepatotoxicity and dangerous CNS or respiratory depression from acetaminophen; tramadol appears to be increased in patients who consume ethanol. Chronic ethanol use can increase acetaminophen-induced hepatotoxicity by inducing cytochrome P450 (CYP) 2E1, which leads to an increased formation of the hepatotoxic metabolite.[583] Also, chronic ethanol use depletes liver glutathione stores.[4934] Furthermore, alcohol withdrawal is associated with a seizure risk, and tramadol appears to increase the risk of seizure development.[5043] Ethanol should not be consumed while taking acetaminophen; tramadol, and acute intoxication with alcohol is a contraindication for acetaminophen; tramadol usage.

Naloxone should be used cautiously in situations of acetaminophen; tramadol overdose. Naloxone administration may increase the risk of seizures in patients receiving tramadol.[5043] Naloxone will reverse some but not all symptoms caused by tramadol overdosage.

An increased incidence of digoxin toxicity has been reported during post-marketing reports with the concurrent use of tramadol and digoxin.[5043] If concurrently used, monitor serum digoxin concentrations, especially after the initiation and cessation of acetaminophen; tramadol.

Significant drug interactions may occur between acetaminophen; tramadol and warfarin. Acetaminophen has been shown to augment the hypoprothrombinemic response to warfarin in a dose-dependent manner when given in large doses for an extended period of time.[1628] [2678] Both INR prolongation and clinical bleeding have been reported during acetaminophen therapy. Also, elevation of prothrombin times during concurrent tramadol and warfarin usage has been reported rarely during the post-marketing period.[5043] Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol.[6685] [6686] The mechanism of the interaction is unknown; tramadol is not highly protein bound and is not known to affect enzymes associated with the metabolism of warfarin. Careful monitoring of a patient's INR is recommended after initiation and cessation of acetaminophen; tramadol. Another alternative analgesic agent may be warranted in patients receiving warfarin.

Sulfinpyrazone can induce hepatic microsomal enzymes that metabolize acetaminophen. Sulfinpyrazone has been shown to increase acetaminophen clearance by roughly 23%.[4939] The risk for acetaminophen hepatotoxicity may be increased due to the formation of higher amounts of toxic acetaminophen metabolites. The risk of acetaminophen hepatotoxicity in patients taking sulfinpyrazone increases with larger acetaminophen doses, particularly overdoses.

Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group.[4064] The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy, such as may occur with acetaminophen; tramadol.

Use of acetaminophen prior to (<72 hours) or concurrently with busulfan may result in decreased clearance of busulfan due to acetaminophen-induced decreases in glutathione levels.[4749] Busulfan is metabolized in the liver through conjugation with glutathione, which is catalyzed by glutathione S-transferase. During high-dose busulfan treatment, glutathione hepatocellular concentrations may be depleted. As the hepatotoxic metabolite of acetaminophen, NAPQI, is inactivated by conjugation with glutathione, the risk of acetaminophen-related hepatotoxicity may be increased.[4943]

Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.[5099]

Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.[5799]

The o-toluidine metabolite of prilocaine can cause the formation of methemoglobin, which can lead to methemoglobinemia. Also, acetaminophen can cause methemoglobinemia (see Adverse Reactions). Patients treated concurrently with prilocaine and acetaminophen; tramadol need to be monitored for the development of hemolytic anemia.

Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. Data suggest that acetaminophen glucuronidation is competitively inhibited by zidovudine, whereas zidovudine glucuronidation is only slightly inhibited by acetaminophen. As more acetaminophen is oxidized, glutathione reserves are needed to detoxify the hepatotoxic intermediate, NAPQI. Thus, the interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism. Also, patients taking an inducer of 2E1 or 1A2 with zidovudine and acetaminophen will have greater production of NAPQI and thus, a greater likelihood of hepatotoxicity.[4928]

Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 [4718] and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen's hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure and death following acetaminophen overdose.[4940]

Excessive sedation and other central nervous system depressant effects may occur with concomitant valerian and acetaminophen; tramadol use. The valerian derivative, dihydrovaltrate binds at barbiturate binding sites. Also, valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain, and the non-volatile monoterpenes (valepotriates) have sedative activity.[4933]

Interactions last revised 12/6/2004 2:09:00 PM

Adverse Reactions

• abdominal pain	• hypertension
• acute generalized exanthematous pustulosis (AGEP)	• hypoprothrombinemia
• agitation	• hypotension
• agranulocytosis	• insomnia
• anaphylactic shock	• interstitial nephritis
• anaphylactoid reactions	• jaundice
• anemia	• maculopapular rash
• angioedema	• methemoglobinemia
• anorexia	• nausea/vomiting
• anxiety	• neonatal abstinence syndrome
• asthenia	• neutropenia
• bronchospasm	• oliguria
• confusion	• pancytopenia
• constipation	• physiological dependence
• contact dermatitis	• pruritus
• diaphoresis	• psychological dependence
• diarrhea	• purpura
• dizziness	• rash (unspecified)
• drowsiness	• renal failure (unspecified)
• dyspepsia	• renal papillary necrosis
• edema	• renal tubular necrosis
• elevated hepatic enzymes	• respiratory depression
• emotional lability	• seizures
• encephalopathy	• serotonin syndrome
• erythema	• sinus tachycardia
• euphoria	• Stevens-Johnson syndrome
• exfoliative dermatitis	• thrombocytopenia
• fetal death	• thrombocytosis
• fever	• tolerance
• flatulence	• toxic epidermal necrolysis
• flushing	• tremor
• hallucinations	• urinary retention
• headache	• urticaria
• hemolysis	• visual impairment
• hemolytic anemia	• withdrawal
• hepatic necrosis	• xerostomia

The more common adverse effects noted over 5 days treatment with acetaminophen; tramadol include: anorexia (3%), constipation (6%), diaphoresis (4%), dizziness (3%), diarrhea (3%), insomnia (2%), nausea (3%), prostatic disorder (2%), pruritus (2%), somnolence or drowsiness (6%) and xerostomia or dry mouth (2%). Abdominal pain, anxiety, asthenia, confusion, dyspepsia, euphoria, flatulence, flushing, hot flushes, nausea/vomiting, nervousness, and tremor were other adverse events noted at an incidence of at least 1%. Emotional lability, hallucinations, and visual impairment were reported in < 1% of patients in Ultracet® trials, but in 1—7% of patients in tramadol trials. Lower doses of acetaminophen; tramadol may be associated with less adverse effects than that seen with higher doses (i.e., nausea and vomiting). Single agent tramadol has been reported to cause less constipation than equipotent doses of acetaminophen and codeine.

Seizures have been reported with tramadol use in humans; patients with an existing seizure disorder are at greatest risk. Seizures have occurred at recommended doses as well as at high doses. Concomitant treatment with drugs that lower the seizure threshold including certain antidepressants (TCAs, and other tricyclic compounds), other opiate agonists, MAOIs, anoretics, or neuroleptics may increase the risk of seizures (see Drug Interactions).[1784] The combination of SSRIs and tramadol has been associated with serotonin syndrome and an increased risk of seizures. One case report details a fatal seizure reaction in an alcoholic adult concomitantly taking tramadol with acetaminophen and several other drugs that increase this risk.[3347] Serotonin syndrome symptoms may include mental status changes, hyperreflexia, elevated temperature, shivering, tremors, agitation, excessive sweating and seizures. In overdose situations, tramadol 's neurotoxicity due to monoamine uptake inhibition appears to be a major problem as opposed to the opioid effects.

Tramadol produces less respiratory depression than morphine. At recommended doses of acetaminophen; tramadol, respiratory depression is not likely to be significant. However, in patients at risk for respiratory depression, alternative non-opioid analgesics should be selected. In tramadol overdose or in combination with anesthetic agents or ethanol, significant respiratory depression may occur. In a prospective case study of reports made to poison control centers of tramadol overdose, the lowest dose of tramadol associated with coma or respiratory depression was 800 mg.[2544]

A case of acquired purpura fulminans developed in a 32 year old woman who was instructed to take acetaminophen 1000 mg every 4—6 hours as needed for pain.[4443] The patient noted rapidly spreading purpuric lesions and edema. Her lesions were nonblanchable and enlarging, and she had multiple purplish-black hemorrhagic and necrotic areas. Purpura fulminans is usually associated with disseminated intravascular coagulation and can occur in patients with inherited or acquired deficiencies of the protein C anticoagulant pathway. The patient developed acquired protein C deficiency from alcohol-induced hepatotoxicity. Fibrin thrombi in the dermal blood vessels, a characteristic finding of purpura fulminans, were present. Discontinuation of alcohol and acetaminophen and administration of vitamin K, heparin, and a systemic antibiotic led to almost complete purpuric lesion and hepatotoxicity resolution in 6 days.

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving initial doses of single agent tramadol. Patients with an allergy to codeine are at increased risk. Other allergic manifestations of tramadol include angioedema, urticaria, pruritus, bronchospasm, rash (unspecified), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Hypersensitivity reactions to acetaminophen may be manifested by urticaria, erythema, generalized pruritus, rash (unspecified), maculopapular rash, and fever. Anaphylactic shock, angioedema, and anaphylactoid reactions have been rarely reported with acetaminophen. Toxic epidermal necrolysis (TEN) occurred in a 7 year old girl after she took 3 doses of acetaminophen 10 mg/kg.[4442] Twelve hours after the last dose, an erythematous rash appeared, which became generalized over the next few hours. The patient developed a fever, low blood pressure and an elevated erythrocyte sedimentation rate and liver function tests. A skin biopsy showed subepidermal blister formation with full-thickness necrolysis of the epidermis and a sparse upper dermal lymphocytic infiltrate. On rechallenge with 10 mg/kg given orally, fever, low blood pressure, and diffuse urticaria and erythema developed 30 minutes after acetaminophen ingestion. In addition to the case of TEN, 4 cases of allergic contact dermatitis (delayed hypersensitivity type) have been reported in the literature.[4444] [4445] Various reactions including generalized pruriginous micropapular eruption, facial edema, generalized pruriginous exanthem, exfoliative dermatitis, and generalized exanthema occurred within several hours after acetaminophen ingestion. Acetaminophen has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38°C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2—3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.[4446]

Physiological dependence (drug craving, drug seeking behavior), psychological dependence, tolerance and withdrawal reactions have been reported during tramadol therapy. Withdrawal reactions have been reported in patients receiving tramadol following naloxone administration. Tramadol can reinitiate physical dependence in patients who have been previously dependent or chronically taking opiate agonists. In patients with a tendency towards drug abuse, a history of drug dependence, or who are taking chronic opiate agonists, treatment with acetaminophen; tramadol is not recommended.

Headache was reported in at least 1% of patients receiving acetaminophen; tramadol. Overuse of combination analgesics such as acetaminophen; tramadol products by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of acetaminophen; tramadol products has been defined as taking 3 or more doses per day more often than 2 days per week.[4043] The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.[4043]

Neonatal abstinence syndrome, fetal death, and still birth have been reported with tramadol in post-marketing reports.

Urinary effects reported in < 1% of patients receiving acetaminophen; tramadol include urinary retention, albuminuria, oliguria, and micturition disorder.

Overdose with acetaminophen; tramadol is a serious and life-threatening event due to toxicity of both the respiratory and hepatic systems. Treatment of tramadol overdose with naloxone is only partially effective and may increase the risk of seizures. Treatment of acetaminophen overdose is with prompt oral administration of N-acetylcysteine. Sinus tachycardia, confusion, and hypertension suggestive of a serotonin syndrome have been reported with overdoses. Respiratory depression may lead to death with tramadol overdose. Acute overdose and excessive chronic use of acetaminophen can lead to hepatotoxicity, manifest as hepatic necrosis, jaundice, bleeding and encephalopathy. After acute acetaminophen overdose, 2 or 3 days pass before maximum liver damage becomes apparent. Nausea/vomiting, anorexia, diaphoresis and abdominal pain usually occur within 2—3 hours after ingestion of toxic doses. Elevated hepatic enzymes, hypoprothrombinemia, and GI bleeding may occur. Agents which affect cytochrome P450 function and ethanol may affect the severity of acetaminophen-induced hepatotoxicity (see Drug Interactions).

The incidence of adverse cardiovascular events with acetaminophen; tramadol is low. Less than 1% of patients developed hypotension, hypertension, or sinus tachycardia.

Acetaminophen can cause acute renal tubular necrosis and chronic analgesic nephropathy, which is characterized by interstitial nephritis and renal papillary necrosis, in patients receiving high doses (e.g., 2.5—10 g/day) chronically or after acute overdose. Acute renal failure may occur in 25—30% of patients secondary to liver dysfunction. Rarely, acute renal failure (unspecified) may occur without severe hepatic toxicity. The risk of renal complications appears to be higher in patients with alcoholism. Chronic acetaminophen use has been implicated as a contributing factor in the decline of renal function in patients with underlying renal disease, including diabetic nephropathy.[541]

Methemoglobinemia can occur after acute overdoses of acetaminophen and can lead to hemolysis thereby causing hemolytic anemia. This can result in cyanosis of the fingernails, skin, and mucosa. Children develop methemoglobinemia more readily than do adults. Other hematologic reactions reported with acetaminophen include agranulocytosis, neutropenia, thrombocytopenia, thrombocytosis, and pancytopenia. Acetaminophen sulfate, a metabolite of acetaminophen, may cause immune-mediated thrombocytopenia. Two adults had improvement in their platelet counts from 45—50 x109/L to 165—325 x109/L within 7—10 days of acetaminophen discontinuation. The sera from each patient had antibodies against platelets in the presence of acetaminophen sulfate.[8205] Agranulocytosis, thrombocytosis, and pancytopenia have only been documented in the literature after acetaminophen overdose. Symptoms such as unusual tiredness or weakness, unusual bleeding or bruising, and unexplained sore throat or fever should be investigated promptly.

Adverse Reactions last revised 8/26/2005 9:55:00 PM

Monitoring Parameters

Monitoring Parameters
•LFTs
•serum creatinine/BUN

Product Information

More information about the following products is available:
• Ultracet®

Patient Education

Acetaminophen; Tramadol tablets

What are acetaminophen; tramadol tablets?
ACETAMINOPHEN; TRAMADOL (Ultracet®) is a combination analgesic that is used to relieve moderate, acute pain such as pain following surgical procedures, including dental surgery. Acetaminophen; tramadol may be used for other types of pain as determined by your health care provider. Generic acetaminophen; tramadol tablets are available.

What should my health care professional know before I take acetaminophen; tramadol?
They need to know if you have any of these conditions:
•an alcohol or drug abuse problem
•blood disease, such as anemia
•breathing difficulty or asthma
•drink more than 3 alcohol-containing drinks per day
•drive or operate machinery or perform hazardous activities
•head injury or brain tumor
•kidney disease
•liver disease
•receiving drugs that lower your ability to fight infection
•seizures (convulsions) or seizure disorder (epilepsy)
•stomach or intestinal problems
•an unusual or allergic reaction to acetaminophen, tramadol, codeine, other pain medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I take this medicine?
Take acetaminophen; tramadol tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. If acetaminophen; tramadol upsets your stomach, take it with food or milk. Do not take more than 2 tablets at a time or more than 8 tablets per day. Higher doses may cause severe side effects, do not take more medication than your prescriber has instructed.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.

Older patients (> 60 years of age) may have a stronger reaction to this medicine, especially if they have kidney or liver disease.

What if I miss a dose?
If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What drug(s) may interact with acetaminophen; tramadol?
•alcohol
•antacids
•antihistamines (commonly found in allergy or cold products)
•busulfan
•bupropion
•cocaine
•diflunisal
•digoxin
•droperidol
•drugs to regulate heart rhythm such as amiodarone, propafenone, quinidine
•furazolidone
•imatinib
•isoniazid, INH
•linezolid
•medicines called MAO inhibitors-phenelzine (Nardil®), tranylcypromine (Parnate®), isocarboxazid (Marplan®), selegiline (Eldepryl®)
•medicines for anxiety, depression, or sleeping problems
•medicines for nausea or vomiting
•medicines for Parkinson's disease such as entacapone, pramipexole, ropinirole or tolcapone
•medicines for mental problems like schizophrenia
•muscle relaxants
•naloxone
•other medicines for pain such as codeine, morphine, nalbuphine, pentazocine, or propoxyphene
•procarbazine
•rifampin
•ritonavir
•seizure medicines
•stimulants such as amphetamine or dextroamphetamine
•St. John's wort
•sulfinpyrazone
•warfarin

What side effects may I notice from taking acetaminophen; tramadol?
Side effects that you should report to your prescriber or health care professional as soon as possible:
Rare or uncommon:
•changes in vision
•difficulty breathing, shortness of breath
•fast or irregular heartbeat
•hallucinations (seeing and hearing things that are not really there)
•not passing urine as often as usual
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•skin rash, itching
•seizures (convulsions)
•yellow tint to your skin or whites of your eyes
More common:
•anxiety, agitation
•vomiting

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
•constipation or diarrhea
•difficulty sleeping
•dizziness, drowsiness
•dry mouth
•false sense of well being, feeling of unreality, mood changes
•headache
•indigestion
•itching
•nausea
•sweating or flushing

What should I watch for while taking acetaminophen; tramadol?
Tell your prescriber or health care professional if your pain does not go away.

Do not drive, use machinery, or do anything that needs mental alertness until you know how acetaminophen; tramadol affects you. Be careful taking other medicines which may also make you tired. This effect may be worse when taking these medicines with acetaminophen; tramadol. Alcohol can increase possible drowsiness, dizziness, confusion and affect your breathing. Do not drink alcoholic beverages while taking tramadol.

Your mouth may get dry. Chewing sugarless gum, sucking hard candy and drinking plenty of water will help.

If you are going to have surgery, tell your prescriber or health care professional that you are taking Ultracet®.

Many non-prescription medicines contain acetaminophen as an ingredient. Additional acetaminophen taken with Ultracet® can be dangerous. Always read the labels carefully to avoid taking an accidental overdose of acetaminophen. Report any possible overdose of acetaminophen; tramadol promptly to your health care provider.

Acetaminophen can affect the results from some blood-sugar tests used by diabetic patients. Check with your prescriber or health care professional before you change your diet or the dose of your diabetic medicine.

Where can I keep my medicine?
Keep out of reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medicine after the expiration date.

NOTE: The information provided above on these medications is not intended to cover all possible uses, precautions, interactions, or adverse effects for these drugs. If you have any further questions about the drug(s) you are taking, please don't hesitate to call us.

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