TREZIX™ Capsules CIII

TREZIX  - acetaminophen, caffeine and dihydrocodeine bitartrate capsule 
WraSer LLC

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TREZIX™ Capsules CIII

Acetaminophen, Caffeine and Dihydrocodeine Bitartrate
356.4 mg / 30 mg / 16 mg

Rx Only


DESCRIPTION:
TREZIX™ capsules are supplied in capsule form for oral administration.
Each red capsule contains:
Acetaminophen...................................................... 356.4 mg
Caffeine .....................................................................30 mg
Dihydrocodeine* bitartrate .......................................... 16 mg

*Warning: may be habit-forming.

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

Acetaminophen - Chemical Structure

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

Caffeine - Chemical Structure

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

Dihydrocodeine bitartrate - Chemical Structure

In addition, each capsule contains the following inactive ingredients: crospovidone, magnesium stearate,
povidone, pregelatinized starch, stearic acid. The capsule is composed of FDandC Red #40, and gelatin.
Imprinting ink is composed of ammonium hydroxide, isopropyl alcohol, n-butyl alcohol, pharmaceutical
glaze (modified) in SD-45, propylene glycol, simethicone, and titanium dioxide.

CLINICAL PHARMACOLOGY:
TREZIX™ capsules contain dihydrocodeine which is a semi-synthetic narcotic analgesic related to codeine, with multiple actions qualitatively similar to those of codeine; the most prominent of these involve the central
nervous system and organs with smooth muscle components. The principal action of therapeutic value is analgesia.
This combination product also contains acetaminophen, a non-opiate, non-salicylate analgesic and antipyretic. This combination product contains caffeine as an analgesic adjuvant. Caffeine is also a CNS and cardiovascular stimulant.

INDICATIONS AND USAGE:
TREZIX capsules are indicated for the relief of moderate to moderately severe pain.

CONTRAINDICATIONS:
This combination product is contraindicated in patients with hypersensitivity to dihydrocodeine, codeine, acetaminophen, caffeine, or any of the inactive components listed above, or any situation where opioids are contraindicated including significant respiratory depression (in unmonitored settings or in the absence of resuscitative equipment), acute or severe bronchial asthma or hypercapnia, and paralytic ileus.

WARNINGS:
Usage in Ambulatory Patients:
Dihydrocodeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

Respiratory Depression:
Respiratory depression is the most dangerous acute reaction produced by opioid agonist preparations, although it is rarely severe with usual doses. Opioids decrease the respiratory rate, tidal volume, minute ventilation, and sensitivity to carbon dioxide. Respiratory depression occurs most frequently in elderly or debilitated patients, usually after large initial doses in non tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. This combination product should be used with caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale and in patients with a substantially decreased respiratory reserve, hypoxia hypercapnia, or respiratory depression. In such patients, alternative non-opioid analgesics should be considered, and opioids should be administered only under careful medical supervision at the lowest effective dose.

Head Injury:
This combination product should be used cautiously in the presence of head injury or increased intracranial pressure. The effects of opioids on pupillary response and consciousness may obscure neurologic signs of increases in intracranial pressure in patients with head injuries. The respiratory depressant effects including carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or other causes of increased intracranial pressures.

Hypotensive Effect:
Dihydrocodeine, like all opioid analgesics, may cause hypotension in patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or who receive concurrent therapy with drugs such as phenothiazines or other agents which compromise vasomotor tone. Acetaminophen, caffeine and dihydrocodeine bitartrate capsules may produce orthostatic hypotension in ambulatory patients. This combination product should be
administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Drug Dependence:
Dihydrocodeine can produce drug dependence of the codeine type and has the potential of being abused (See DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS:
General:
Selection of patients for treatment with TREZIX® capsules should be governed by the same principles that apply to the use of similar opioid/non-opioid fixed combination analgesics. As with any such opioid analgesic, the dosing regimen should be adjusted for each patient (See DOSAGE AND ADMINISTRATION). This combination product should be used with caution in elderly or debilitated patients or those with any of the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); asthma; central nervous system depression or coma; chronic obstructive pulmonary disease; decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis); delirium tremens; head injury; hypotension; increased intracranial pressure; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis. The benefits and risks of using opioids in patients taking monoamine oxidase inhibitors and in those with a history of drug abuse should be carefully considered. The administration of an analgesic containing an opioid may obscure the diagnosis or clinical course in patients with acute abdominal conditions. This combination product may aggravate convulsions in patients with convulsive disorders and, like all opioids, may induce or aggravate seizures in some clinical settings.
Acetaminophen is relatively non-toxic at therapeutic doses, but should be used with caution in patients with severe renal or hepatic disease.
Care should be observed when using large doses of acetaminophen in malnourished patients or those with a history of chronic alcohol abuse because they may be more susceptible to hepatic damage similar to that observed with toxic overdosage.
Caffeine in high doses may produce central nervous system and cardiovascular stimulation and gastrointestinal irritation.

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

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

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

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

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

Information for Patients/Caregivers:
Patients receiving TREZIX® capsules should be given the following information:
1. Patients should be advised that TREZIX® capsules may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
2. Patients should be advised to report adverse experiences occurring during therapy.
3. Patients should be advised not to adjust the dose of TREZIX® capsules withoutconsulting the prescribing professional.
4. Patients should not combine TREZIX® capsules with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.
5. Women of child bearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
6. Patients should be advised that TREZIX® capsules are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

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

Labor and Delivery:
TREZIX® capsules are not recommended for use by women during and immediately before labor and delivery because oral opioids may cause respiratory depression in the newborn.

Nursing Mothers:
Dihydrocodeine bitartrate, acetaminophen and caffeine are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from this combination product, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:
Safety and effectiveness of TREZIX® capsules in pediatric patients have not been established.

Geriatric Use:
TREZIX® capsules should be given with caution to the elderly.

Hepatic Impairment:
TREZIX™ capsules should be given with caution to patients with hepatic insufficiency. Since dihydrocodeine is metabolized by the liver and since acetaminophen potentially causes hepatotoxicity, the effects of this combination product should be monitored closely in such patients.

Renal Impairment:
TREZIX™ capsules should be used with caution and at reduced dosage in the presence of impaired renal function.

Pancreatic/Biliary Tract Disease:
Opioids may cause spasms of the sphincter of Oddi and should be used with caution in patients with biliary tract disease including pancreatitis.

ADVERSE REACTIONS:
Dihydrocodeine:
The most frequently observed adverse reactions include light-headedness, dizziness, drowsiness, headache, fatigue, sedation, sweating, nausea, vomiting, constipation, pruritus, and skin reactions. With the exception of constipation, tolerance develops to most of these effects. Other reactions that have been observed with dihydrocodeine or other opioids include respiratory depression, orthostatic hypotension, cough suppression, confusion, diarrhea, miosis, abdominal pain, dry mouth, indigestion, anorexia, spasm of biliary tract, and urinary retention. Physical and psychological dependence are possibilities. Hypersensitivity reactions (including anaphylactoid reactions), hallucinations, vivid dreams, granulomatous interstitial nephritis, severe narcosis and acute renal failure have been reported rarely during dihydrocodeine administration.

Acetaminophen:
Acetaminophen in therapeutic doses rarely causes adverse reactions. The most serious adverse reaction is hepatoxicity from overdosage (see OVERDOSAGE). Thrombocytopenia, leukopenia, pancytopenia, neutropenia, thrombocytopenic purpura, and agranulocytosis have been reported in patients receiving acetaminophen or p-aminophenol derivatives. Hypersensitivity reactions including urticarial or erythematous skin reactions, laryngeal edema, angioedema, or anaphylactoid reactions are rare.

Caffeine:
Adverse reactions associated with caffeine use include anxiety, anxiety neurosis, excitement, headaches, insomnia, irritability, lightheadedness, restlessness, tenseness, tremor, extrasystoles, palpitations, tachycardia, diarrhea, nausea, stomach pain, vomiting, diuresis, urticarcia, scintillating scotoma, and tinnitus.

DRUG ABUSE AND DEPENDENCE:
This combination product is subject to the provisions of the Controlled Substance Act and has been placed in Schedule III.
Dihydrocodeine can produce drug dependence of the codeine type and therefore has the potential of being abused. Like other opioid analgesics, dihydrocodeine may produce subjected effects other than analgesia (e.g., euphoria, relaxation), which may contribute to abuse by some patients. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of dihydrocodeine, and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral opioid analgesic medications.
Symptoms of dihydrocodeine withdrawal consist of irritability, restlessness, insomnia, diaphoresis, anxiety and palpitations.
Prolonged, high intake of caffeine may produce tolerance and habituation. Physical signs of withdrawal, such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation.

OVERDOSAGE:
Following an acute overdosage with TREZIX™ capsules, toxicity may result from the dihydrocodeine, acetaminophen, or, less likely, caffeine component. An overdose is a potentially lethal polydrug overdose situation, and consultation with a regional Poison Control Center is recommended. A listing of the poison control centers can be found in standard references such as the Physician's Desk Reference®.

Signs and Symptoms and Laboratory Findings:
Toxicity from dihydrocodeine is typical of opioids and includes pinpoint pupils, respiratory depression, and loss of consciousness. Convulsions, cardiovascular collapse, and death may occur. A single case of acute rhabdomyolysis associated with an overdose of dihydrocodeine has been reported. With acetaminophen, dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may occur. Early symptoms of hepatotoxicity include nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours after ingestion. Acute caffeine poisoning may cause insomnia, restlessness, tremor, delirium, tachycardia, extrasystoles, and seizures.

Because overdose information on this combination product is limited, it is unclear which of the signs and symptoms of toxicity would manifest in any particular overdose situation.

Treatment:
Immediate treatment of an overdosage of TREZIX™ capsules includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced with syrup of ipecac, if the patient is alert and has adequate laryngeal reflexes. Oral activated charcoal should follow. The first dose of charcoal should be accompanied by an appropriate cathartic. Gastric lavage may be necessary. Hypotension is usually hypovolemic and should be treated with fluids. Endotracheal intubation and artificial respiration may be necessary. Peritoneal or hemodialysis may be necessary. If hypoprothrombinemia occurs, Vitamin K should be administered.
A pure opioid antagonist, such as naloxone or nalmefene, is a specific antidote against respiratory depression which results from opioid overdose. Opioid antagonists should not be given in the absence of clinically significant respiratory or circulatory depression secondary to opioid overdose. They should be administered cautiously to persons who are known, or suspected to be, physically dependent on any opioid agonist including Acetaminophen, caffeine and dihydrocodeine bitartrate capsules. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The prescribing information for the specific opioid antagonist should be consulted for details of their proper use. In adults and adolescents, regardless of the quantity of acetaminophen reported to have been ingested, acetylcysteine should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion. It is not advisable to await the plasma concentration determination of acetaminophen before administering acetylcysteine. Serum liver enzyme levels should be measured. Therapy in children involves a similar treatment scheme; however, a regional Poison Control Center should be contacted. No specific antidote is available for caffeine. In addition to the supportive measures above, administration of demulcents such as aluminum hydroxide gel may diminish gastrointestinal irritation. Seizures may be treated with intravenous diazepam or a barbiturate.

DOSAGE AND ADMINISTRATION:
The usual adult dosage is two (2) TREZIX® capsules orally every four (4) hours, as needed. Dosage should be adjusted according to the severity of the pain and the response of the patient. No more than two (2) capsules should be taken in a 4-hour period. No more than five (5) doses, or ten (10) capsules should be taken in a 24-hour period.

HOW SUPPLIED:
TREZIX® capsules, containing acetaminophen 356.4 mg, caffeine 30 mg and dihydrocodeine* bitartrate 16 mg (*Warning: May be habit-forming), are supplied in bottles of 100 capsules (NDC #66992-340-10).
Also, TREZIX® is supplied in single-capsule sample blister packs (NDC #66992-340-01).
Capsules are imprinted “TREZIX” on the red cap in white ink.

Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container with a child-resistant closure. Protect from moisture.

Rx Only

Manufactured for:
WraSer Pharmaceuticals
Ridgeland, MS 39157

13001 Rev. October, 2007

Physician’s Desk Reference® is the registered trademark of Thomson Healthcare, Inc.

WraSer
Pharmaceuticals

NDC 66992-340-10

TREZIX
356.4mg acetaminophen, 30mg caffeine
and 16mg dihydrocodeine bitartrate CIII

Rx ONLY       WARNING: May be habit-forming.

100 CAPSULES

Image of Product Label


TREZIX 
acetaminophen, caffeine, dihydrocodeine bitartrate   capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)66992-340
Route of AdministrationORALDEA ScheduleCIII    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN356.4 mg
CAFFEINE (CAFFEINE) CAFFEINE30 mg
DIHYDROCODEINE BITARTRATE (DIHYDROCODEINE) DIHYDROCODEINE BITARTRATE16 mg
Inactive Ingredients
Ingredient NameStrength
CROSPOVIDONE 
MAGNESIUM STEARATE 
POVIDONE 
STARCH, CORN 
STEARIC ACID 
Product Characteristics
ColorredScore no score
ShapeCAPSULESize20mm
FlavorImprint Code TREZIX
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
166992-340-10100 CAPSULE In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA04068809/01/2009

Labeler - WraSer LLC (121828334)
Revised: 01/2010WraSer LLC