Phrenilin

PHRENILIN- butalbital, acetaminophen, caffeine and codeine phosphate capsule
Valeant Pharmaceuticals North America

Rx Only

DESCRIPTION

Phrenilin® with Caffeine and Codeine Capsules (butalbital, acetaminophen, caffeine and codeine phosphate) are supplied in capsule form for oral administration.

Each capsule contains:
codeine phosphate, USP …………………………………………….30 mg
butalbital, USP ………………………………………………………50 mg
caffeine, USP ………………………………………………………..40 mg
acetaminophen, USP ……………………………………………….325 mg

Codeine phosphate [morphine-3-methyl ether phosphate (1:1) (salt) hemihydrate, C18 H24 NO7 P, anhydrous mw 397.37], a white, odorless, crystalline powder, is a narcotic analgesic and antitussive.

Image from Drug Label Content

Butalbital (5-allyl-5-isobutylbarbituric acid, C11 H16 N2 O3 , mw224.26),a slightly bitter, white, odorless, crystalline powder is a short to intermediate-acting barbiturate

Image from Drug Label Content

Caffeine (1,3,7,-trimethylxanthine, C8 H10 N4 O2 , mw 194.19), a bitter, white crystalline powder, is a central nervous system stimulant.

Image from Drug Label Content

Acetaminophen (4′-hydroxyacetanilide, C8 H9 NO2 , mw 151.17), a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic.

Image from Drug Label Content

Active Ingredients: codeine phosphate, USP, butalbital, USP caffeine, USP and acetaminophen, USP.

Inactive Ingredients: benzyl alcohol, butylparaben, colloidal silicone dioxide, D&C Red #33, edetate calcium disodium, FD&C blue #1, gelatin, lactose monohydrate, magnesium stearate, methylparaben, propylparaben, sodium lauryl sulfate, sodium propionate, titanium dioxide. The imprinting ink contains: ammonium hydroxide, black iron oxide — synthetic, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, potassium hydroxide, propylene glycol, shellac — pharmaceutical grade.

CLINICAL PHARMACOLOGY

Phrenilin® with Caffeine and Codeine Capsules (butalbital, acetaminophen, caffeine and codeine phosphate) is a combination drug product intended as a treatment for tension headache.

Butalbital, Acetaminophen and Caffeine Capsules USP consists of a fixed combination of butalbital 50 mg, acetaminophen 325 mg and caffeine 40 mg. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood.

Pharmacokinetics: The behavior of the individual components is described below.

Codeine: Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 to 6 hours.

(See OVERDOSAGE for toxicity information.)

Butalbital: Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.

Elimination of butalbital is primarily via the kidney (59% — 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5 (3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated.

The in-vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20 to 45%) reported with other barbiturates such as phenobarbital, pentobarbital and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells.

(See OVERDOSAGE for toxicity information.)

Caffeine: Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.

Caffeine is cleared through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methyl-xanthine and 1-methyluric acid. Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug.

(See OVERDOSAGE for toxicity information.)

Acetaminophen: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 — 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

(See OVERDOSAGE for toxicity information.)

Phrenilin Indications and Usage

Phrenilin® with Caffeine and Codeine (butalbital, acetaminophen, caffeine and codeine phosphate capsules) are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.

Evidence supporting the efficacy and safety of Phrenilin® with Caffeine and Codeine (butalbital, acetaminophen, caffeine and codeine phosphate capsules) in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.

CONTRAINDICATIONS

Phrenilin® with Caffeine and Codeine (butalbital, acetaminophen, caffeine and codeine phosphate capsules) are contraindicated under the following conditions:

  • Hypersensitivity or intolerance to acetaminophen, caffeine, butalbital, or codeine.

  • Patients with porphyria.

WARNINGS

In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Phrenilin® with Caffeine and Codeine (butalbital, acetaminophen, caffeine and codeine phosphate) is not recommended.

PRECAUTIONS

General

Phrenilin® with Caffeine and Codeine (butalbital, acetaminophen, caffeine and codeine phosphate) should be prescribed with caution in certain special-risk patients such as the elderly or debilitated, and those with severe impairments of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy.

Ultra-rapid Metabolizers of Codeine

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6* 2×2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regiments, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing.

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, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See PRECAUTIONS-Nursing Mothers)

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