Acetaminophen, Caffeine and Dihydrocodeine Bitartrate         

320.5 mg / 30 mg / 16 mg

Rx Only                                                CIII

TREZIX™ capsules are supplied in capsule form for oral administration.

Each red capsule contains:

Acetaminophen...........................................320.5 mg

Caffeine ..........................................................30 mg

Dihydrocodeine bitartrate ...............................16 mg

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

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:

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



In addition, each capsule contains the following inactive ingredients: crospovidone, magnesium stearate, povidone, pregelatinized starch, stearic acid. The capsule is composed of FD&C 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.

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.

TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsulesare indicated for the relief of moderate to moderately severe pain.

Dihydrocodeine-containing products are contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.

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.

Hepatotoxicity:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death.  Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.



The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.



Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine:

Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see Error! Hyperlink reference not valid.].

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or  *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert dihydrocodeine into its active metabolite, dihydromorphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum dihydromorphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage].

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly  sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Dihydrocodeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications].

When prescribing dihydrocodeine-containing products, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Overdosage].

Hypersensitivity/Anaphylaxis:

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen.  Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticarial, rash, pruritus, and vomiting.  There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention.  Instruct patients to discontinue TREZIX™ immediately and seek medical care if they experience these symptoms.  Do not prescribe TREZIX™ for patients with acetaminophen allergy.



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 nontolerant 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).

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, urticaria, scintillating scotoma, and tinnitus.

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.

Following an acute overdosage with TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules, toxicity may result from the dihydrocodeine or the acetaminophen. Toxicity due to the caffeine component is less likely, due to the relatively small amounts in this formulation. 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: Toxicity from dihydrocodeine poisoning include the opioid triad of: 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. In acetaminophen overdosage: dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion. Acute caffeine poisoning may cause insomnia, restlessness, tremor, delirium, tachycardia, and extrasystoles.



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

A single or multiple drug overdose with TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules is a potentially lethal polydrug overdose, and consultation with a regional Poison Control Center is recommended.  Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, and vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to dihydrocodeine, parenteral naloxone is a specific and effective antagonist. Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation.  Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.  To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected.  Intravenous NAC may be administered when circumstances preclude oral administration.



Vigorous supportive therapy is required in severe intoxication.  Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

The usual adult dosage is two (2) TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) 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.

TREZIX™ capsules, containing acetaminophen 320.5 mg, caffeine 30 mg and dihydrocodeine bitartrate 16 mg, are supplied in bottles of 30(NDC #63187-705-30), 60(NDC #63187-705-60), 90(NDC #63187-705-90), 100 (NDC #63187-705-00) and 120 capsules (NDC #63187-705-72)

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 LLC

Ridgeland, MS 39157

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

13001 Rev. May 2014

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

NDC 63187-705-60

TREZIXTM CIII

(acetaminophen, caffeine and dihydrocodeine bitartrate capsules 320.5mg/30mg/16mg)

Rx ONLY

60 CAPSULES

DESCRIPTION:                                                                  

Each red capsule contains:

Acetaminophen .................................. 320.5 mg

Caffeine ................................................... 30 mg

Dihydrocodeine Bitartrate ....................... 16 mg

USUAL DOSAGE: See package insert for full prescribing information.

WARNING: Keep this and all medications out of the reach of children.

PHARMACIST: Dispense in a tight, light-resistant container with a child-resistant closure. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Manufactured for:

WraSer Pharmaceuticals

Ridgeland, MS 39157

www.wraser.com

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

13001 Rev. 5/14

WraSer PHARMACEUTICALS