CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY
CATEGORIES: Antiglaucomatous Agents; EENT Drugs; Eye, Ear, Nose, & Throat Preparations; FDA Approved 1984 Oct; Glaucoma; Intraocular Pressure; Miotics; Mydriasis; Ocular Hypertension; Ophthalmics; Parasympathomimetic Agents; Pregnancy Category C
BRAND NAMES: Carpinol*; Carpo*; Faring*; Liocarpina*; Miocarpine*; Ocusert Pilo; Pilocardine*; Pilokarpin*; Pilomann*; Piloptic*; Pilosyst*; Pilotonina*; Spersacarpine*; Spersakarpin*; Thilo*
* Foreign brand name outside U.S.
FORMULARIES: Medi-Cal; WHO
Miocarpine* brand of PILOCARPINE

DESCRIPTION
Ocusert® pilocarpine system is an elliptically shaped unit designed for continuous release of pilocarpine following placement in the cul-de-sac of the eye. Clinical evaluation in appropriate patients has demonstrated therapeutic efficacy of the system in the eye for one week. Two strengths are available, Pilo-20 and Pilo-40.
Ocusert systems contain a core reservoir consisting of pilocarpine and alginic acid. Pilocarpine is designated chemically as 2(3H)-Furanone, 3-ethyldihydro-4((1-methyl-1H-imidazol-5-yl) methyl)-, (3S-cis)-.
The core is surrounded by a hydrophobic ethylene/vinyl acetate (EVA) copolymer membrane which controls the diffusion of pilocarpine from the Ocusert system into the eye. The Pilo-40 membrane contains di(2-ethylhexyl) phthalate, which increases the rate of diffusion of pilocarpine across the EVA membrane. Of the total content of pilocarpine in the Pilo-20 or Pilo-40 system (5 mg or 11 mg, respectively), a portion serves as the thermodynamic diffusional energy source to release the drug and remains in the unit at the end of the week’s use. The alginic acid component of the core is not released from the system. The readily visible white margin around the system contains titanium dioxide. The Pilo-20 system is 5.7 x 13.4 mm on its axes and 0.3 mm thick; the Pilo-40 system is 5.5 x 13 mm on its axes and 0.5 mm thick.
Release Rate Concept: With the Ocusert system form of therapy, the particular strength is described by the rated release, the mean release rate of drug from the system over seven days, in micrograms per hour. To cover the range of drug therapy needed to control the increased intraocular pressure associated with the glaucomas, two rated releases of pilocarpine from the Ocusert system are available, 20 and 40 micrograms per hour, for one week.
During the first few hours of the seven day time course, the release rate is higher than that prevailing over the remainder of the one-week period. The system releases drug at three times the rated value in the first hours and drops to the rated value in approximately six hours. A total of 0.3 mg to 0.7 mg pilocarpine (Pilo-20 or Pilo-40, respectively) is released during this initial six-hour period (one drop of 2% pilocarpine ophthalmic solution contains 1 mg pilocarpine). During the remainder of the seven day period the release rate is within ±20% of the rated value.
Miocarpine* brand of PILOCARPINE

CLINICAL PHARMACOLOGY

Pilocarpine is released from the Ocusert system as soon as it is placed in contact with the conjunctival surfaces. Pilocarpine is a direct acting parasympathomimetic drug which produces pupillary constriction, stimulates the ciliary muscle, and increases aqueous humor outflow facility. Because of its action on ciliary muscle, pilocarpine induces transient myopia, generally more pronounced in younger patients. In association with the increase in outflow facility, there is a decrease in intraocular pressure.
Preclinical Results: The levels of 14C-pilocarpine in the ocular tissues of rabbits following Ocusert system and eyedrop administration have been determined. The Ocusert system produces constant low pilocarpine levels in the ciliary body and iris. Following 14C-pilocarpine eyedrop treatment, the initial levels of pilocarpine in the cornea, aqueous humor, ciliary body and iris are 3 to 5 times higher than the corresponding levels with the Ocusert system, declining over the next six hours to approximately the tissue concentrations maintained by the Ocusert system. In contrast, in the conjunctiva, lens, and vitreous the 14C-pilocarpine concentrations remain consistently high from eyedrops and do not return to the constant low levels maintained by the Ocusert system. Pilocarpine does not accumulate in ocular tissues during Ocusert system use. These studies in rabbits have not been done in humans.
Clinical Results: The ocular hypotensive effect of both the Pilo-20 and Pilo-40 systems is fully developed within 1 1/2 to 2 hours after placement in the cul-de-sac. A satisfactory ocular hypotensive response is maintained around-the-clock. Intraocular pressure reduction for an entire week is achieved with the Ocusert system from either 3.4 mg or 6.7 mg pilocarpine (20 or 40 mcg/hour times 24 hours/day times 7 days, respectively), as compared with 28 mg administered as a 2% ophthalmic solution four times a day.
During the first several hours after insertion of an Ocusert pilocarpine system into the conjunctival cul-de-sac, induced myopia may occur. In contrast to the fluctuating and high levels of induced myopia typical of pilocarpine administration by eyedrop, the amount of induced myopia with Ocusert systems decreases after the first several hours to a low baseline level, approximately 0.5 diopters or less, which persists for the therapeutic life of the Ocusert system. Pilocarpine-induced miosis approximately parallels the induced myopia.
Of the 302 patients who used the Ocusert system in clinical studies for more than two weeks, 229 (75%) preferred it to previously used pilocarpine eyedrops. This percentage increased with further wearing experience.

Miocarpine* brand of PILOCARPINE

INDICATIONS
Ocusert pilocarpine system is indicated for control of elevated intraocular pressure in pilocarpine responsive patients. Clinical studies have demonstrated Ocusert system efficacy in certain glaucomatous patients.
The patient should be instructed on the use of the Ocusert system and should read the package insert instructions for use. The patient should demonstrate to the ophthalmologist his ability to place, adjust and remove the units.
Concurrent Therapy: Ocusert systems have been used concomitantly with various ophthalmic medications. The release rate of pilocarpine from the Ocusert system is not influenced by carbonic anhydrase inhibitors, epinephrine or timolol ophthalmic solutions, fluorescein, or anesthetic, antibiotic, or antiinflammatory steroid ophthalmic solutions. Systemic reactions consistent with an increased rate of absorption from the eye of an autonomic drug, such as epinephrine, have been observed. The occurrence of mild bulbar conjunctival edema, which is frequently present with epinephrine ophthalmic solutions, is not influenced by the Ocusert pilocarpine system.
Miocarpine* brand of PILOCARPINE

CONTRAINDICATION
Ocusert pilocarpine system is contraindicated where pupillary constriction is undesirable, such as for glaucomas associated with acute inflammatory disease of the anterior segment of the eye, and glaucomas occurring or persisting after extracapsular cataract extraction where posterior synechiae may occur.
Miocarpine* brand of PILOCARPINE

WARNING
Patients with acute infectious conjunctivitis or keratitis should be given special consideration and evaluation prior to the use of the Ocusert pilocarpine system.
Damaged or deformed systems should not be placed or retained in the eye. Systems believed to be associated with an unexpected increase in drug action should be removed and replaced with a new system.
Miocarpine* brand of PILOCARPINE

PRECAUTIONS
General
Ocusert pilocarpine system safety in retinal detachment patients and in patients with filtration blebs has not been established. The conjunctival erythema and edema associated with epinephrine ophthalmic solutions are not substantially altered by concomitant Ocusert pilocarpine system therapy. The use of pilocarpine drops should be considered when intense miosis in desired in certain ocular conditions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity and reproduction studies in animals have been conducted with the Ocusert system.
Pregnancy Category C
Although the use of the Ocusert pilocarpine system has not been reported to have adverse effect on pregnancy, the safety of its use in pregnant women has not been absolutely established. While systemic absorption of pilocarpine from the Ocusert system is highly unlikely, pregnant women should use it only if clearly needed.
Nursing Mothers
It is not known whether pilocarpine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when the Ocusert system is used by a nursing woman.
Pediatric Use
Safety and effectiveness in children have not been established.
Miocarpine* brand of PILOCARPINE

DRUG INTERACTION
Although ophthalmic solutions have been used effectively in conjunction with the Ocusert system, systemic reactions consistent with an increased rate of absorption from the eye of an autonomic drug, such as epinephrine, have been observed. In rare instances, reactions of this type can be severe.
Miocarpine* brand of PILOCARPINE

ADVERSE REACTIONS
Ciliary spasm is encountered with pilocarpine usage but is not a contraindication to continued therapy unless the induced myopia is debilitating to the patient. Irritation from pilocarpine has been infrequently encountered and may require cessation of therapy depending on the judgment of the physician. True allergic reactions are uncommon but require discontinuation of therapy should they occur. Corneal abrasion and visual impairment have been reported with use of the Ocusert System.
Although withdrawal of the peripheral iris from the anterior chamber angle by miosis may reduce the tendency for narrow angle closure, miotics can occasionally precipitate angle closure by increasing the resistance to aqueous flow from posterior to anterior chamber. Miotic agents may also cause retinal detachment; thus, care should be exercised with all miotic therapy especially in young myopic patients.
Some patients may notice signs of conjunctival irritation, including mild erythema with or without a slight increase in mucous secretion when they first use Ocusert pilocarpine systems. These symptoms tend to lessen or disappear after the first week of therapy. In rare instances a sudden increase in pilocarpine effects has been reported during system use.
Miocarpine* brand of PILOCARPINE

DOSAGE AND ADMINISTRATION
Initiation of Therapy: A patient whose intraocular pressure has been controlled by 1% or 2% pilocarpine eyedrop solution has a higher probability of pressure control with the Pilo-20 system than a patient who has used a higher strength pilocarpine solution and might require Pilo-40 therapy. However, there is no direct correlation between the Ocusert system (Pilo-20 and Pilo-40) and the strength of pilocarpine eyedrop solutions required to achieve a given level of pressure lowering. The Ocusert system reduces the amount of drug necessary to achieve adequate medical control; therefore, therapy may be started with the Ocusert Pilo-20 system irrespective of the strength of pilocarpine solution the patient previously required. Because of the patient’s age, family history, and disease status or progression, however, the ophthalmologist may elect to begin therapy with the Pilo-40. The patient should then return during the first week of therapy for evaluation of his intraocular pressure, and as often thereafter as the ophthalmologist deems necessary.
If the pressure is satisfactorily reduced with the Ocusert Pilo-20 system the patient should continue its use, replacing each unit every 7 days. If the physician desires intraocular pressure reduction greater than that achieved by the Pilo-20 system, the patient should be transferred to the Pilo-40 system. If necessary, an epinephrine ophthalmic solution of a carbonic anhydrase inhibitor may be used concurrently with Ocusert system.
After a satisfactory therapeutic regimen has been established with the Ocusert pilocarpine system, the frequency of follow-up should be determined by the ophthalmologist according to the status of the patient’s disease process.
Placement and Removal of the Ocusert System: The Ocusert system is readily placed in the eye by the patient, according to patient instructions provided in the package. The instructions also describe procedures for removal of the system. It is strongly recommended that the patient’s ability to manage the placement and removal of the system be reviewed at the first patient visit after initiation of therapy.
Since the pilocarpine-induced myopia from the Ocusert systems may occur during the first several hours of therapy (average of 1.4 diopters in a group of young subjects), the patient should be advised to place the system into the conjunctival cul-de-sac at bedtime. By morning the induced myopia is at a stable level (about 0.5 diopters or less in young subjects).
Sanitary Handling: Patients should be instructed to wash their hands thoroughly with soap and water before touching or manipulating the Ocusert system. In the event a displaced unit contacts unclean surfaces, rinsing with cool tap water before replacing is advisable. Obviously bacteriologically contaminated units should be discarded and replaced with a fresh unit.
Ocusert System Retention in the Eye: During the initial adaptation period, the Ocusert unit may slip out of the conjunctival cul-de-sac onto the cheek. The patient is usually aware of such movement and can replace the unit without difficulty.
In those patients in whom retention of the Ocusert unit is a problem, superior cul-de-sac placement is often more desirable. The Ocusert unit can be manipulated from the lower to the upper conjunctival cul-de-sac by a gentle digital massage through the lid, a technique readily learned by the patient. If possible the unit should be moved before sleep to the upper conjunctival cul-de-sac for best retention. Should the unit slip out of the conjunctival cul-de-sac during sleep, its ocular hypotensive effect following loss continues for a period of time comparable to that following instillation of eyedrops. The patient should be instructed to check for the presence of the Ocusert unit before retiring at night and upon arising.

STORAGE AND HANDLING
Store under refrigeration (36o – 46oF).
(91/04)
(91/04)
Miocarpine* brand of PILOCARPINE
HOW SUPPLIED – EQUIVALENTS NOT AVAILABLE:
Insert – Ophthalmic – 20 mcg/hr
8’s $34.20 OCUSERT PILO, Alza 17314-4064-03*
Insert – Ophthalmic – 40 mcg/hr
8’s $34.20 OCUSERT PILO, Alza 17314-4086-03*

CATEGORIES, BRAND NAMES, FORMULARIES & COST OF THERAPY
CATEGORIES: Analgesics; Antipyretics; Central Nervous System Agents; DEA Class CV; FDA Approval Pre 1982; Narcotic Agonist-Antagonist; Narcotics, Synthetics & Combinations; Opiate Agonists (Controlled); Opiate Partial Agonists; Pain; Pregnancy Category C
BRAND NAMES: Buprenex; Buprex*; Finibron*; Lepetan*; Norphin*; Prefin*; Temgesic*
* Foreign brand name outside U.S.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

DESCRIPTION
Buprenex (buprenorphine hydrochloride) is a narcotic under the Controlled Substances Act due to its chemical derivation from thebaine. Chemically, it is 17-(cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy-alpha-methyl-6, 14-ethenomorphinan-7-methanol, hydrochloride (5alpha, 7alpha(S)). Buprenorphine hydrochloride is a white powder, weakly acidic and with limited solubility in water. Buprenex is a clear, sterile, injectable agonist-antagonist analgesic intended for intravenous or intramuscular administration. Each ml of Buprenex contains 0.324 mg buprenorphine hydrochloride (equivalent to 0.3 mg buprenorphine), 500 mg anhydrous dextrose, water for injection and HCl to adjust pH. Buprenorphine hydrochloride has the molecular formula, C29H41NO4HCl.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

CLINICAL PHARMACOLOGY
Buprenex is a parenteral opioid analgesic with 0.3 mg Buprenex being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened.
The limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. In postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2-7.2 hours (mean 2.2 hours) after intravenous administration of 0.3 mg of buprenorphine. A single, ten-patient, pharmacokinetic study of doses of 3mcg/kg in children (age 5-7 years) showed a high inter-patient variability, but suggests that the clearance of the drug may be higher in children than in adults. This is supported by at least one repeat-dose study in postoperative pain that showed an optimal interdose interval of 4-5 hours in pediatric patients as opposed to the recommended 6-8 hours in adults.
Buprenorphine, in common with morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. Studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.
Mechanism of Analgesic Action: Buprenex exerts its analgesic effect via high affinity binding to mc subclass opiate receptors in the central nervous system. Although Buprenex may be classified as a partial agonist, under the conditions of recommended use it behaves ver much like classical mc agonists such as morphine. One unusual property of Buprenex observed in in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.
Narcotic Antagonist Activity: Buprenorphine demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test.
Cardiovascular Effects: Buprenex may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients.
Effects on Respiration: Under usual conditions of use in adults, both Buprenex and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, Buprenex (0.3 mg buprenorphine) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10 mg). (See WARNINGS.)
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE
INDICATIONS
Buprenex is indicated for the relief of moderate to severe pain.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

CONTRAINDICATION
Buprenex should not be administered to patients who have been shown to be hypertensive to the drug.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

WARNING
Impaired Respiration: As with other potent opioids, clinically significant respiratory depression may occur within the recommended dose range in patients receiving therapeutic doses of buprenorphine. Buprenex should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, corpulmonate, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression). Particular caution is advised if Buprenex is administered to patients taking or recently receiving drugs with CNS/respiratory depressant effects. In patients with the physical and/or pharmacological risk factors, above, the dose should be reduced by approximately one-half.
NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENEX. THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED.
Interaction with Other Central Nervous System Depressants: Patients receiving Buprenex in the presence of other narcotic analgesics, general anesthetics, antihistamines, benzodiazepines, phenothiazines, other tranquilizers, sedative hypnotics or other CNS depressants (including alcohol) may exhibit increased CNS depression. When such combined therapy is contemplated, it is particularly important that the dose of one or both agents be reduced.
Head Injury and Increased Intracranial Pressure: Buprenex, like other potent analgesics, may itself elevate cerebrospinal fluid pressure and should be used with caution in head injury, intracranial lesions and other circumstances where cerebrospinal pressure may be increased. Buprenex can produce miosis and changes in the level of consciousness which may interfere with patient evaluation.
Use in Ambulatory Patients: Buprenex may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Therefore, Buprenex should be administered with caution to ambulatory patients who should be warned to avoid such hazards.
Use in Narcotic-Dependent Patients: Because of the narcotic antagonist activity of Buprenex, use in the physically dependent individual may result in withdrawal effects.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

PRECAUTIONS
General: Buprenex should be administered with caution in the elderly, debilitated patients, in children and those with severe impairment of hepatic, pulmonary, or renal function, myxedema or hypothyroidism; adrenal cortical insufficiency (e.g., Addison’s disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
Because Buprenex is metabolized by the liver, the activity of Buprenex may be increased and/or extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance.
Buprenex has been shown to increase intracholedochal pressure to a similar degree as other opioid analgesics, and thus should be administered with caution to patients with dysfunction of the biliary tract.
Information for Patients: The effects of Buprenex, particularly drowsiness, may be potentiated by other centrally acting agents such as alcohol or benzodiazepines. It is particularly important that in these circumstances patients must not drive or operate machinery. Buprenex has some pharmacologic effects similar to morphine which in susceptible patients may lead to self administration of the drug when pain no longer exists. Patients must not exceed the dosage of Buprenex prescribed by their physician. Patients should be urged to consult their physician if other prescription medications are currently being used or are prescribed for future use.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The effects of Buprenex on fertility and gestation indices were investigated in rats by the subcutaneous and intramuscular routes at doses 10 to 100 times the proposed human doses. Dystocia was noted in dams treated with 1000 times the human dose. No effects on fertility or gestation were noted in these Segment I studies.
Pregnancy: Pregnancy Category C. Reproduction studies have been performed in the rat at doses which ranged from 10 to 1000 times the proposed human dose by the subcutaneous and intramuscular routes and 160 times the proposed human dose by the intravenous route. By the intramuscular route, Buprenex produced mild but statistically significant (p < 0.05) post-implantation losses and early fetal deaths at 10 and 100 but not 1000 times the proposed human dose. No fetal malformations were noted in rats at any dose when Buprenex was administered by subcutaneous, intramuscular, or intravenous routes. In rabbits, intramuscularly administered Buprenex produced a dose-related trend for rib formation which attained statistical significance (p < 0.01) at 1000 times the proposed human dose. By the intravenous route, doses in rats of 40 and 160 times the proposed human dose of Buprenex caused a slight increase in post-implantation losses that may have been treatment-related. No major fetal malformations were noted in drug treated groups when administered by intramuscular or intravenous routes.
There are no adequate and well-controlled studies in pregnant women. Buprenex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The safety of Buprenex given during labor and delivery has not been established.
Nursing Mothers: An apparent lack of milk production during general reproduction studies with Buprenex in rats caused decreased viability and lactation indices. It is unknown at this time whether or not Buprenex is excreted in human milk. Despite the lack of specific knowledge on this issue, it is reasonable to assume that Buprenex will enter human milk and caution should be exercised in the sue of Buprenex when it is administered to nursing mothers.
Pediatric Use: The safety and effectiveness of Buprenex have been established for children between 2 and 12 years of age. Use of Buprenex in children is supported by evidence from adequate and well controlled trials of Buprenex in adults, with additional data from studies of 960 children ranging in age from 9 months to 18 years of age. Data is available from a pharmacokinetic study, several controlled clinical trials, and several large post-marketing studies and case series. The available information provides reasonable evidence that Buprenex may be used safely in children ranging from 2-12 years of age, and that it is of similar effectiveness in children as in adults.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

DRUG INTERACTION
Drug interactions common to other potent opioid analgesics also may occur with Buprenex. Particular care should be taken when Buprenex is used in combination with central nervous system depressant drugs (see WARNINGS). Although specific information is not presently available, caution should be exercised when Buprenex is used in combination with MAO inhibitors. There have been reports of respiratory and cardiovascular collapse in patients who received therapeutic doses of diazepam and Buprenex. A suspected interaction between Buprenex. A suspected interaction between Buprenex and phenprocoumon resulting in purpura has been reported.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

ADVERSE REACTIONS
The most frequent side effect in clinical studies involving 1133 patients was sedation which occurred in approximately two-thirds of the patients. Although sedated, these patients could be easily aroused to an alert state.
Other less frequent adverse reactions occurring in 5-10% of the patients were:
Nausea
Dizziness/Vertigo
Occurring in 1-5% of the patients:
Sweating
Hypotension
Vomiting
Miosis
Headache
Nausea/Vomiting
Hypoventilation
The following adverse reactions were reported to have occurred in less than 1% of the patients:
CNS Effect: confusion, blurred vision, euphoria, weakness/fatigue, dry mouth, nervousness, depression, slurred speech, paresthesia.
Cardiovascular: hypertension, tachycardia, bradycardia.
Gastrointestinal: constipation.
Respiratory: dyspnea, cyanosis.
Dermatological: pruritus.
Ophthalmological: diplopia, visual abnormalities.
Miscellaneous: injection site reaction, urinary retention, dreaming, flushing/warmth, chills/cold, tinnitus, conjunctivitis, Wenckebach block, and psychosis.
Other effects observed infrequently include malaise, hallucinations, depersonalization, coma, dyspepsia, flatulence, apnea, rash, amblyopia, tremor and pallor.
The following reactions have been reported to occur rarely: loss of appetite, dysphoria/agitation, diarrhea, urticaria, and convulsions/lack of muscle coordination.
In the United Kingdom, buprenorphine hydrochloride was made available under monitored release regulation during the first year of sale, and yielded data from 1736 physicians on 9123 patients (17,120 administrations). Data on 240 children under the age of 18 years were included in this monitored release program. No important new adverse effects attributable to buprenorphine hydrochloride were observed.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

DRUG ABUSE AND DEPENDENCE
Buprenorphine hydrochloride is a partial agonist of the morphine type; i.e., it has certain opioid properties which may lead to psychic dependence of the morphine type due to an opiate-like euphoric component of the drug. Direct dependence studies have shown little physical dependence upon withdrawal of the drug. However, caution should be used in prescribing to individuals who are known to be drug abusers or ex-narcotic addicts. The drug may not substitute in acutely dependent narcotic addicts due its antagonist component and may induce withdrawal symptoms.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

OVERDOSAGE
Manifestations: Clinical experience with Buprenex overdosage has been insufficient to define the signs of this condition at this time. Although the antagonist activity of buprenorphine may become manifest at doses somewhat above the recommended therapeutic range, doses in the recommended therapeutic range may produce clinically significant respiratory depression in certain circumstances.
Treatment: The respiratory and cardiac status of the patients should be monitored carefully. Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Doxapram, a respiratory stimulant, may be used. NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENEX. THEREFORE, AS WITH OTHER POTENT OPIOIDS, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

DOSAGE AND ADMINISTRATION
Adults: The usual dosage for persons 13 years of age and over is 1 ml of Buprenex (0.3 mg buprenorphine) given by deep intramuscular or slow (over at least 2 minutes) intravenous injection at up to 6-hour intervals, as needed. Repeat once (up to 0.3 mg) if required, 30 to 60 minutes after initial dosage, giving consideration to previous dose pharmacokinetics, and thereafter only as needed. In high-risk patients (e.g., elderly, debilitated, presence of respiratory disease, etc.) and/or in patients where other CNS depressants are present, such as in the immediate postoperative period, the dose should be reduced by approximately one-half. Extra caution should be exercised with the intravenous route of administration, particularly with the initial dose.
Occasionally, it may be necessary to administer single doses of up to 0.6 mg to adults depending on the severity of the pain and the response of the patient. This dose should only be given I.M. and only to adult patient who are not in a high risk category (see WARNINGS and PRECAUTIONS). At this time, there are insufficient data to recommend single doses greater than 0.6 mg for long-term use.
Children: Buprenex has been used in children 2-12 years of age at doses of between 2-6 micrograms/kg of body weight, or the use of a repeat or second dose at 30-60 minutes (such as is used in adults). Since there is some evidence that not all children clear buprenorphine faster than adults, fixed interval or “round-the-clock” dosing should not be undertaken until the proper inter-dose interval has been established by clinical observation of the child. Physicians should recognize that, as with adults, some pediatric patients may not need to be remedicated for 6-8 hours.
Safety and Handling: Buprenex is supplied in sealed ampules and poses no known environmental risk to health care providers. Accidental dermal exposure should be treated by removal of any contaminated clothing and rinsing the affected area with water.
Buprenex is a potent narcotic, and like all drugs of this class has been associated with abuse and dependence among health care providers. To control the risk of diversion, it is recommended that measures appropriate to the health care setting be taken to provide rigid accounting, control of wastage, and restriction of access.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

HOW SUPPLIED
Buprenex (buprenorphine hydrochloride) is supplied in clear glass snap-ampuls of 1 ml (0.3 mg buprenorphine).
NDC 12496-0757-1
Avoid excessive heat (over 104oF or 40oC.) Protect from prolonged exposure to light.
CAUTION: Federal law prohibit dispensing without prescription.
(Reckitt & Colman, 1/93, 912801)
(93/01)
Prefin* brand of BUPRENORPHINE HYDROCHLORIDE

HOW SUPPLIED – EQUIVALENTS NOT AVAILABLE:
Injection, Solution – Intramuscular; Intravenous – 0.3 mg/ml
10’s $24.25 BUPRENEX, Reckitt & Colman 12496-0757-01

Parke-Davis
Ketamine HCl
Parenteral General Anesthetic

Action And Clinical Pharmacology: Ketamine is a cataleptic, analgesic and anesthetic agent devoid of sedative or hypnotic properties, distinguishing it from the commonly used barbiturates.
It produces an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes and normal or slightly enhanced skeletal muscle tone. Mild cardiac stimulation and occasionally respiratory depression occur.
The anesthetic state produced by ketamine has been termed dissociative anesthesia’ in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centres and pathways (reticular activating and limbic systems).
Ketamine is rapidly absorbed following parenteral administration. Animal experiments indicated that ketamine was rapidly distributed into body tissues, with relatively high concentrations appearing in body fat, liver, lung and brain; lower concentrations were found in the heart, skeletal muscle and blood plasma. Placental transfer of the drug was found to occur in pregnant dogs and monkeys. No significant degree of binding to serum albumin was found with ketamine.
Studies in human subjects resulted in the mean recovery of 91% of the dose in the urine and 3% in the feces. Peak plasma levels averaged about 0.75 µg/mL and CSF levels were about 0.2 µg/mL, 1 hour after dosing.
Ketamine undergoes N-demethylation and hydroxylation of the cyclohexanone ring, with the formation of water-soluble conjugates which are excreted in the urine. Further oxidation also occurs with the formation of a cyclohexanone derivative. The unconjugated N-demethylated metabolite was found to be less than one sixth as potent as ketamine. The unconjugated demethyl cyclohexanone derivative was found to be less than one tenth as potent as ketamine. Repeated doses of ketamine administered to animals did not produce any detectable increase in microsomal enzyme activity.
Indications And Clinical Uses: As the sole anesthetic agent for recommended diagnostic and surgical procedures. Although best suited to short procedures, ketamine can be used, with additional doses, for longer procedures.
Note: If skeletal muscle relaxation is desired, a muscle relaxant should be used. In surgical procedures involving visceral pain pathways, ketamine should be supplemented with an agent which obtunds visceral pain.
For the induction of anesthesia prior to the administration of other general anesthetic agents.
To supplement low potency agents such as nitrous oxide.

Contra-Indications: History of cerebrovascular accident; cases where a significant elevation of blood pressure would constitute a serious hazard, such as in patients with severe hypertension; severe cardiac decompensation; in surgery of the pharynx, larynx, or bronchial tree unless adequate muscle relaxants are used; hypersensitivity to the drug.
Precautions: Ketamine is for use only by or under the direction of physicians and oral surgeons experienced in administering general anesthetics and in maintenance of an airway and in the control of respiration.
Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.
Barbiturates and ketamine, being chemically incompatible because of precipitate formation, should not be injected from the same syringe.
Barbiturates and narcotics, being CNS depressants, may prolong recovery time if used concurrently with ketamine.
Respiratory depression may occur with overdosage or too rapid administration of ketamine, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to administration of analeptics.
An increase in cerebrospinal fluid pressure has been reported following the administration of ketamine. Therefore, special caution should be exercised when using ketamine in cases with preexisting elevated intracranial pressure, and in those cases with normal intracranial pressure in which, in the opinion of the physician, a rise in such pressure would entail special risks.
Pregnancy: Although animal studies of teratogenicity, fertility, and reproduction indicated the safety of ketamine, its safe use in human pregnancy has not been established.
Because pharyngeal reflexes are maintained, mechanical stimulation of the pharynx should be avoided unless adequate muscle relaxants are used. Precautions should be taken in patients with upper respiratory infection because of the increased danger of respiratory difficulties, such as laryngospasm, in these cases.
Resuscitative equipment should be available and ready for use.
The initial i.v. dose should be administered over a period of 60 seconds. More rapid administration may result in respiratory depression and enhanced pressor response.
During recovery from anesthesia the patient may go through a phase of emergence reaction characterized by vivid dreams, confusion (with or without psychomotor activity), excitement, irrational behavior and occasionally hallucinations. In 12 283 procedures, postanesthetic emergence responses were broken down into parameters and the incidence of reaction is shown in Table I.
Table I indicates that emergence reactions are more common in the 15 to 35 year group.
The reactions tabled above occurred in the majority of instances in patients in whom droperidol or diazepam had not been used as premedications.
Long-term follow up observations of 221 patients (140 with ketamine, 81 with other anesthetic agents) have not revealed any residual psychological effects.
The incidence of emergence reactions may be reduced if verbal, tactile and visual stimulation of the patient is avoided during the recovery period, certainly until the patient is fully conscious and able to be returned to the ward. These precautions do not preclude the monitoring of vital signs.
Hypnotic doses of ultrashort acting thiobarbiturates (50 to 100 mg i.v.) can be used to terminate severe emergence reactions. Diazepam, 5 mg i.v., has also been used to terminate emergence reactions.
During anesthesia the eyelids may remain retracted. During recovery they close. Premature stimulation during recovery in the presence of nystagmus and diplopia may precipitate retching, nausea, or frank vomiting.
Purposeless movements of extremities may occur during the course of anesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.

Adverse Reactions: Cardiovascular: Ketamine may cause a temporary augmentation of the pulse rate and blood pressure. Elevation of blood pressure begins shortly after injection, reaches a maximum within a few minutes and usually returns to preanesthetic values within 15 minutes after injection. The median peak rise has ranged from 20 to 25% of preanesthetic values. Depending on the condition of the patient, this elevation of blood pressure may be considered a beneficial effect, or in others, an adverse reaction. If elevation of blood pressure would be considered adverse to the patient, the benefit to risk ratio should be carefully determined. Maintaining or moderately increasing blood pressure may be beneficial to some patients, as those in shock or those in whom reduction in blood pressure is contraindicated (see Precautions).
Hypotension, arrhythmia, and bradycardia have rarely been observed.

Respiratory: Respiration is not greatly affected. Mild stimulation sometimes occurs, but respiratory depression, moderate and transient (less than 30 seconds), also occurs in a small percentage of patients. Laryngospasm and other forms of airway obstruction have occurred during ketamine anesthesia.
Psyche: During emergence from anesthesia the patient may go through a phase of vivid dreaming, with or without psychomotor activity, manifested by confusion and irrational behavior (see Precautions). These reactions are transient and have been observed less often in children than in adults. They appear to be similar to those observed following the use of other general anesthetic agents.
Tonic and clonic movements sometimes resembling convulsive seizures have occurred in a few patients receiving ketamine. These movements do not imply a light plane and are not indicative of the need for additional doses of the anesthetic.
EEG recordings were made in 14 patients receiving ketamine. Although 1 of these patients exhibited slight twitching of the arms and legs, none showed EEG changes to suggest seizure reactions.
Epileptiform attacks have been observed in a few patients following ketamine administration. However, ketamine has been used successfully in patients known to be suffering from epilepsy.

Gastrointestinal: Anorexia, nausea, or vomiting are minimal, allowing the great majority of patients to take liquids by mouth shortly after regaining consciousness.
Increased salivation may occur unless an antisialagogue is used.
Ophthalmic: Blurred vision and nystagmus are not uncommon findings during the recovery period.
Ketamine causes a small transient increase in intraocular pressure. However, it has been used in patients with glaucoma without causing any deterioration in this condition.

General: Except for rare reports of local pain and exanthema at the injection site, ketamine is well tolerated by the patient when administered either by the i.v. or i.m. route. Transient erythema and morbilliform rash have been reported.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Respiratory depression can result from an overdosage of ketamine. Supportive ventilation should be employed. Mechanical support of respiration that will maintain adequate blood oxygen saturation and carbon dioxide elimination is preferred to administration of analeptics.
Ketamine has a wide margin of safety; several instances of unintentional administration of overdoses of ketamine (up to 10 times of the usually required dose) have been followed by prolonged but complete recovery.

Dosage And Administration: Ketamine has been safely used alone when the stomach was not empty. However, since the need to use supplementary anesthetic or muscle relaxant agents cannot always be predicated, it is preferable not to give anything by mouth for at least six hours before elective surgery. Ketamine is recommended for use in patients whose stomach is not empty when in the judgment of the physician the benefits of the drug outweigh the possible hazards.
Atropine, scopolamine, or other antisecretory agents should be given at an appropriate interval prior to induction.
Certain drugs such as droperidol or diazepam have been used i.m. in an attempt to reduce the incidence of emergence reactions: sufficient data have not yet been accumulated to constitute thorough documentation. The incidence of emergence reactions is reduced as experience with the drug is gained.
As with other general anesthetic agents, the individual response to ketamine is somewhat varied depending on the dose, route of administration, and age of patient, so that dosage recommendation cannot be absolutely fixed. The drug should be titrated to the patient’s requirements.
Because of rapid induction following the initial i.v. injection, the patient should be in a supported position during administration.
The onset of action of ketamine is rapid; an i.v. dose of 2 mg/kg (1 mg/lb) usually produces surgical anesthesia within 30 seconds after injections, with the anesthetic effect usually lasting 5 to 10 minutes. If a longer effect is desired, additional increments can be administered i.v. or i.m. to maintain anesthesia without producing significant cumulative effects.
I.M. doses, from experience primarily in children, in a range of 9 to 13 mg/kg (4 to 6 mg/lb) usually produce surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.

Ketamine as sole anesthetic agent:

Induction: I.V.: The initial dose of ketamine administered i.v. may range from 1.0 to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required to produce 5 to 10 minutes of surgical anesthesia has been 2.0 mg/kg (1 mg/lb). Ketamine should be administered slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.
I.M.: The initial dose of ketamine administered i.m. may range from 6.5 to 13.0 mg/kg (3 to 6 mg/lb). A dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgical anesthesia.)
Maintenance: Increments of 50% to the full induction dose, either i.v. or i.m. may be repeated as needed for maintenance of anesthesia. Nystagmus, movements in response to stimulation, and vocalization may indicate lightening of anesthesia.
Ketamine used prior to administration of other general anesthetics: Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained.
When ketamine is used as an induction agent, prior to the administration of other general anesthetic agents:
1. The full induction dose of ketamine should be given i.v. over 60 seconds.
2. At the completion of the induction dose of ketamine, the anesthetist should proceed immediately with the chosen general anesthetic procedure. A second dose of ketamine (half the original induction dose) may be required at 5 to 8 minutes following the initial induction dose when using an agent such as methoxyflurane where some considerable time is required for full surgical anesthesia to be established with the gaseous anesthetic. Otherwise lightening in the depth of anesthesia may occur and the patient may enter the stage of excitement, associated with vocalization and purposeful movements.

Recovery: Following the procedure the patient should be observed but left undisturbed. This does not preclude the monitoring of vital signs.
Availability And Storage: 10 mg: Each mL contains: ketamine HCl equivalent to 10 mg ketamine base. Steri-Vials of 20 mL.
50 mg: Each mL contains: ketamine HCl equivalent to 50 mg ketamine base. Steri-Vials of 10 mL.
The solution for i.v. or i.m. use contains 1:10 000 benzethonium chloride as a preservative (pH 3.5 to 5.5). The 10 mg/mL solution has been made isotonic with sodium chloride (2.6 mg/5 mL).

Wyeth-Ayerst
Trihexyphenidyl HCl
Antispasmodic

Indications And Clinical Uses: As an adjunct in the treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa. Additionally, it is indicated for the control of extrapyramidal disorders caused by central nervous system drugs such as the dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones.
Manufacturers’ Warnings In Clinical States: Patients to be treated with trihexyphenidyl should have a gonioscope evaluation and close monitoring of intraocular pressures at regular periodic intervals.
Precautions: Maintain patients with cardiac, liver, kidney or hypertensive disorders under close observation. Patients undergoing prolonged therapy should be subjected to constant and careful long-term observation to avoid allergic and other untoward reactions. Trihexyphenidyl should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Geriatric patients, particularly over the age of 60, frequently develop increased sensitivity to parasympatholytic drugs and hence, require strict dosage regulation. Incipient glaucoma may be precipitated by trihexyphenidyl. Tardive dyskinesia may appear in some patients on long-term therapy with antipsychotic drugs or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. However, parkinsonism and tardive dyskinesia often coexist in patients receiving chronic neuroleptic treatment, and anticholinergic therapy with trihexyphenidyl may relieve some of these parkinsonism symptoms.

Adverse Reactions: Dryness of mouth, blurred vision, dizziness, mild nausea or nervousness will be experienced by 30 to 50% of all patients. These sensations, however, are much less troublesome with trihexyphenidyl than with belladonna alkaloids and are usually less disturbing than unalleviated parkinsonism. Such reactions tend to become less pronounced, and even to disappear, as treatment continues. Even before these reactions have remitted spontaneously, they may often be controlled by careful adjustment of dosage form, amount of drug, or interval between doses.
Isolated instances of suppurative parotitis secondary to excessive dryness of the mouth, skin rashes, dilatation of the colon, paralytic ileus, and certain psychiatric manifestations such as delusions and hallucinations, plus one doubtful case of paranoia have been rarely reported with trihexyphenidyl.
Patients with arteriosclerosis or with a history of idiosyncrasy to other drugs may exhibit reactions of mental confusion, agitation, disturbed behavior, or nausea and vomiting. Such patients should be allowed to develop a tolerance through the initial administration of a small dose and gradual increase in dose until an effective level is reached. If a severe reaction should occur, administration of the drug should be discontinued for a few days and then resumed at a lower dosage. Psychiatric disturbances can result from indiscriminate use (leading to overdosage) to sustain continued euphoria.

Potential untoward effects associated with the use of any atropine like drugs include constipation, drowsiness, urinary hesitancy or retention, tachycardia, dilatation of the pupil, increased intraocular tension, weakness, vomiting, and headache.

The occurrence of angle closure glaucoma due to long term trihexyphenidyl treatment has been reported.
Dosage And Administration: Should be individualized. The initial dosage should be low and then increased gradually, especially in patients over 60 years of age.
Whether trihexyphenidyl may best be given before or after meals should be determined by the way the patient reacts. Postencephalitic patients, who are usually more prone to excessive salivation, may prefer to take it after meals and may, in addition, require small amounts of atropine which, under such circumstances, is sometimes an effective adjuvant. If trihexyphenidyl tends to dry the mouth excessively, it may be better to take it before meals, unless it causes nausea. If taken after meals, the thirst sometimes induced can be allayed by mint candies, chewing gum or water.
Parkinsonism: 1 mg orally the first day; increased by 2 mg daily at intervals of 3 to 5 days, up to 6 to 10 mg daily. Best tolerated in divided doses at mealtime.
Drug Induced Parkinsonism: The size and frequency of doses of trihexyphenidyl HCl needed to control drug induced extrapyramidal reactions notably reserpine, and phenothiazine derivatives, must be determined empirically. The total daily dosage usually ranges between 5 and 15 mg although, in some cases, these reactions have been satisfactorily controlled on as little as 1 mg daily. It may be advisable to commence therapy with a single 1 mg dose. If the extrapyramidal manifestations are not controlled in a few hours, the subsequent doses may be progressively increased until satisfactory control is achieved. Satisfactory control may sometimes be more rapidly achieved by temporarily reducing the dosage of the tranquilizer or instituting trihexyphenidyl HCl therapy and then adjusting dosage of both drugs until the desired ataractic effect is retained without onset of the extrapyramidal reactions.
It is sometimes possible to maintain the patient on a reduced trihexyphenidyl HCl dosage after the reactions have remained under control for several days. Instances have been reported in which these reactions have remained in remission for long periods after therapy was discontinued.

Concomitant use of trihexyphenidyl with levodopa: When trihexyphenidyl is used concomitantly with levodopa, the usual dose of each may need to be reduced. Careful adjustment is necessary, depending on side effects and degree of symptom control. Trihexyphenidyl dosage of 3 to 6 mg daily, in divided doses, is usually adequate.
Concomitant use of trihexyphenidyl with other parasympathetic inhibitors: Trihexyphenidyl may be substituted, whole or in part, for other parasympathetic inhibitors. The usual technique is partial substitution initially, with progressive reduction in the other medication as the dose of trihexyphenidyl is increased.
The total daily intake of tablets or elixir is tolerated best if divided into 3 doses and taken at mealtimes. High doses (>10 mg daily) may be divided into 4 parts with 3 doses administered at mealtimes and the fourth at bedtime.

Availability And Storage: Elixir: Each 5 mL of clear, lime flavored preparation contains: trihexyphenidyl HCl 2 mg with methylparaben 4 mg, propylparaben 1 mg, citric acid 9 mg and alcohol 214 mg as preservatives. Tartrazine-free. Bottles of 450 mL.

Tablets: 2 mg: Each round, white, scored tablet, engraved “LL, A11” and “Artane 2”, contains: trihexyphenidyl HCl 2 mg. Tartrazine-free. Bottles of 100.
5 mg: Each round, white, scored tablet, engraved “LL, A12” and “Artane 5”, contains: trihexyphenidyl HCl 5 mg. Tartrazine-free. Bottles of 100.
Reviewed 1995

Wyeth-AyerstMetoclopramide HClUpper Gastrointestinal Tract Motility Modifier – Antiemetic

Availability And Storage: Injectable: Each 2 mL vial contains: metoclopramide HCl 10 mg (5 mg/mL). Also contains sodium chloride 8.5 mg/mL. Cartons of 10.
Each 10 mL vial for i.v. infusion (with dilution) contains: metoclopramide HCl 50 mg (5 mg/mL). Also contains sodium chloride 8.5 mg/mL. Cartons of 10. (For the prophylaxis of nausea and vomiting associated with cancer chemotherapeutic regimens that include ciplatin as a component.)
Each 30 mL single use vial for i.v. infusion (with dilution) contains: metoclopramide HCl 150 mg (5 mg/mL). Also contains sodium chloride 8.5 mg/mL. Cartons of 10. (For the prophylaxis of nausea and vomiting associated with cancer chemotherapeutic regimens that include cisplatin as a component.)
Liquid: Each mL of orange-colored, chocolate-flavored liquid contains: metoclopramide HCl 1 mg. Also contains parabens. Energy: 51.9 kJ (12.4 kcal)/5 mL. Bottles of 100 mL.
Tablets: 5 mg: Each blue, compressed, capsule-shaped tablet, engraved “Reglan” on one side and AYERST 5 on the other, contains: metoclopramide HCl 5 mg. Energy: <1 kJ (<1 kcal). Bottles of 100 and 500.
10 mg: Each blue, scored, compressed tablet, engraved AYERST, contains: metoclopramide HCl 10 mg. Energy: <1 kJ (<1 kcal). Bottles of 100 and 500.
All dosage forms are gluten-, lactose-, sulfite- and tartrazine-free.

Alcon
Balanced Salt Solution
Ocular Irrigation Therapy

Availability And Storage: Each 15 mL self dispensing plastic squeeze bottle with adapter for Luer-Lok hub irrigating needles in sterile packaging (Steri Unit, single dose), or each polyvinyl chloride bag of 250 or 500 mL, in sterile packaging, contains: sodium chloride 0.64%, potassium chloride 0.075%, magnesium chloride 0.03%, calcium chloride 0.048%, sodium acetate 0.39% and sodium citrate 0.17%. Contains no preservatives. Discard unused portions.

Description: Enlast cream contains components that are safe for the human body and effective in the treatment of premature ejaculation. The product can also temporarily reduce the sensitivity of the male genital organs, which helps prolong ejaculation. This cream can be applied with condoms.

Composition:

Enlast cream for premature ejaculation contains benzocaine – a substance that reduces the sensitivity of the male genital organs. The drug has been approved by the US Food and Drug Administration (FDA) as a means to prevent premature ejaculation.

Indications:

• Avoid premature ejaculation;
• Temporarily reduce the sensitivity of the male genital region;
• Prolong ejaculation during sexual intercourse;
• Reduce oversensitivity during sexual intercourse.

Dosage:

10 to 12 drops a few minutes prior to sexual activity.

Instructions for Use:

1. Open up the jar and take 10 to 12 drops onto your hand;
2. Apply the cream to the shaft and head of the penis prior to sexual activity;
3. After sexual intercourse be sure to wash off the cream.

Enlast cream works immediately, so you don’t have to wait. As an added bonus, the cream works as a great lubricant for sex.

Adverse Reactions:

Some men may experience allergic reactions to some of the ingredients of Enlast cream. While the cream is generally side effect free, you’d still better consult your doctor before using the preparation.

Other:

Premature ejaculation is a condition that may develop due to a variety of factors. If you have tried Enlast cream with no positive results, stop use the product and contact your doctor for more help. Use this cream as directed on the label. If you notice a rash or your sexual partner develops any irritation, stop using the cream immediately.

General Information

Indications

Produced with top-ranking dermatologists, this innovative cream assists to get rid of irritated skin, intensely moisturizing and helping previse extra-dry skin recurrence. It’s rich with a ceramide, an essential lipid, naturally observed within the skin that play a major role in keeping and restoring the skin’s protective function. Aveeno is clinically prescribed to assist to decrease the itching and irritation of eczema. Plus, it’s dermatologist tested, and gentle enough for babies and children.

Ingredients

Locks in moisture and helps prevent dry skin.

The AVEENO® brand is most trusted for its use of natural ingredients. Oat is the natural ingredient most recommended by dermatologists. As a skin protectant active ingredient, oatmeal can help restore skin’s normal pH and aid in the maintenance of skin’s moisture barrier to help prevent and protect dry skin.

General Information

Indications

Cytomel (sodium lyoteronin) is prescribed to patients suffering from hypothyroidism (a decrease in thyroid function), a disease in which thyroid gland does not produce enough thyroid hormone. Since this hormone is very important in metabolism regulation and energy metabolism in body, a low level of this hormone can lead to:

• weight gain;
• hair loss;
• sensitivity to cold;
• other manifestations.

Treatment with this drug is aimed at eliminating these symptoms. In addition, this drug is used in treatment of thyroid (goiter) enlargement, analysis of hyperthyroidism and treatment of autoimmune thyroiditis. However, this drug can not be used to reduce body weight.

Dosing and Administration

Before treatment beginning with tablets of Cytomel (sodium lyoteronin) it is necessary to consult the attending physician. The preparation contains 25 μg of active substance. In most cases, patients treated with hypothyroidism receive 25 μg once a day. A marked change in symptoms is usually observed 2 weeks after treatment onset. Dosage may be increased depending on patient’s response to ongoing treatment. Other diseases may require other dosage regimens, so before starting treatment it is necessary to undergo a medical examination from attending physician.

Side Effects

Possible side effects when taking Cytomel (sodium lyotyronin) include:

• anxiety;
• decreased body weight;
• gastric colic;
• temporary hair loss;
• sweating and sensitivity to heat.

Inform your doctor about any side effects. In rare cases, serious side effects may develop. If you have chest pain or other serious symptoms, you should seek emergency medical attention.

Special Instructions

Patients with normal thyroid function are contraindicated taking this medication for purpose of treating obesity. There is a risk of a serious reaction and possible death if the drug is taken in combination with other diet pills.

Before starting treatment, tell your doctor if you have a history of any of the following diseases:

• kidney disease;
• diabetes;
• any cardiovascular disease;
• chest pain;
• heart rhythm disturbances;
• heart attack;
• decreased pituitary function;
• adrenal glands.

General Information

Brand Name:

ACCOLATE®

Manufacturer:

Zeneca

Scientific Name:

Zafirlukast

Application:

Leukotriene Receptor Antagonist

Pharmacology

Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in 1 study to be 25 to 100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of 3 leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness. In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.

Clinical Studies: Three double-blind, randomized, placebo-controlled, 13-week clinical trials in 1 380 patients with mild to moderate asthma demonstrated that zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue b2-agonist use, FEV1, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline b-agonist requirement of approximately 4 to 5 puffs of salbutamol/day. The results of the largest of the trials are shown in Table I. In a second and smaller study, the effect of zafirlukast on most efficacy parameters was comparable to the active control (inhaled sodium cromoglycate 1 600 µg 4 times/day) and superior to placebo at endpoint for decreasing rescue b-agonist use. In these trials, improvement in asthma symptoms occurred within 1 week of initiating treatment with zafirlukast. The role of zafirlukast in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as needed, inhaled b2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.

Pharmacokinetics: Absorption: Zafirlukast is rapidly absorbed following oral administration. The absolute bioavailability of zafirlukast is unknown. Peak plasma concentrations are achieved 3 hours after dosing. In 2 separate studies, one using a high fat and the other a high protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%. Plasma Kinetics and Disposition: The mean terminal elimination half-life of zafirlukast is approximately 10 hours in both normal subjects and patients with asthma. Steady-state plasma concentrations of zafirlukast are proportional to the dose and predictable from single dose pharmacokinetic data. In the concentration range of 0.25 to 10 µg/mL, zafirlukast is >99% bound to plasma proteins, predominantly albumin.

Biotransformation: Zafirlukast is extensively metabolized. Following oral administration of a radiolabeled dose, urinary excretion accounts for approximately 10% of the dose and the remainder is excreted in feces. Unmetabolized zafirlukast is not detected in urine. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast are formed through the cytochrome P450 2C9 (CYP2C9) enzyme pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved plasma concentrations. The metabolites of zafirlukast found in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity.

Special Populations: Geriatrics: Cross-study comparisons in patients ranging from 7 years to greater than 65 years of age show that mean dose (mg/kg) normalized AUC and Cmax increase and plasma clearance (Cl) decreases with increasing age. In patients above 65 years of age, there is an approximately 2- to 3-fold greater Cmax and AUC compared to young adult patients.

Hepatic Impairment: In a study of patients with hepatic impairment (biopsy-proven cirrhosis), there was a 50 to 60% greater Cmax and AUC compared to normal subjects.

Renal Impairment: Based on a cross-study comparison, there are no apparent differences in the pharmacokinetics of zafirlukast between renally impaired patients and normal subjects.

Indications

For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.

Contraindications

In patients who have previously experienced hypersensitivity to the product or any of its ingredients.

Warnings

Zafirlukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Warfarin Interaction: Warfarin coadministration with zafirlukast produces clinically significant increases in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see Precautions, Drug Interactions).

Hepatic Effects: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. Most of these cases have been observed in asymptomatic patients at doses 4 times higher than the recommended dose, and return to the normal range after a variable period of time upon discontinuation of zafirlukast therapy. Liver function test abnormalities could represent early evidence of hepatotoxicity that may occur with prolonged administration. This risk appears to be greater in women. Rare cases of symptomatic hepatitis and hyperbilirubinemia, without other attributable causes, have occurred in patients who have received the recommended doses of zafirlukast (40 mg/day). In these patients, the liver enzymes returned to normal or near normal after stopping zafirlukast. If clinical signs or symptoms of liver dysfunction (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, and “flu-like symptoms) are noted, it is reasonable to recommend that standard liver tests be obtained and the patient managed accordingly. A decision to discontinue zafirlukast should be individualized to the patient’s condition, weighing the risk of hepatic dysfunction against the clinical benefit of zafirlukast to the patient.

Precautions

General: Zafirlukast should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast therapy can be continued during acute exacerbations of asthma. Zafirlukast is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician.

Eosinophilic Conditions: When oral steroid reduction is considered, caution is required. Reduction of the oral steroid dose, in some asthma patients on zafirlukast therapy, has been followed, in rare cases, by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, sometimes presenting as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. A causal relationship with zafirlukast has not been established.

Hepatic Effects: See Warnings. Children: The efficacy and safety of zafirlukast in children under 12 years has not been established.

Carcinogenesis and Mutagenicity: In 2-year oral carcinogenicity studies, zafirlukast was administered at daily doses of 10 to 300 mg/kg to mice and 40 to 2 000 mg/kg to rats. At 300 mg/kg/day male mice had an increased incidence of hepatocellular adenomas and female mice showed a greater incidence of whole body histocytic sarcomas. The plasma concentrations at these tumorigenic doses were approximately 220 times maximum recommended human daily oral dose. Male and female rats given 2 000 mg/kg/day had an increased incidence of urinary bladder transitional cell papillomas. The plasma concentrations at these tumorigenic doses were approximately 200 times the plasma concentrations in humans at the maximum recommended human daily oral dose. The clinical significance of these findings for the long-term use of zafirlukast is unknown. No mutagenic potential was evident in point mutation assays or chromosomal aberrations clastogenic assays.

Reproduction and Fertility: Reproduction and fertility studies in rats showed no effect on fertility due to zafirlukast at doses up to 2 000 mg/kg (approximately 400 times the maximum recommended human daily oral dose on mg/mbasis). In the 1-year toxicity studies in dogs, zafirlukast produced an increase in absolute and relative uterine and ovarian weights at an oral dose of 150 mg/kg, resulting in approximately 85 times the systemic exposure (AUC0-12h) in humans at the maximum recommended human oral daily dose.

Pregnancy: The safety of zafirlukast in human pregnancy has not been established. The potential risks should be weighed against the benefits of continuing therapy during pregnancy; zafirlukast should be used only if clearly needed. No teratogenicity was observed in the following species for the given oral doses (the approximate equivalence to the maximum recommended human daily oral dose on a mg/mbasis is given in brackets): mice 1 600 mg/kg/day (160 times); rats 2 000 mg/kg/day (400 times); cynomolgus monkeys 2 000 mg/kg/day (800 times). At these doses, maternal toxicity was manifested in rats (as deaths and increased incidence of early fetal resorption), and cynomolgus monkeys (as spontaneous abortions). There are no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, zafirlukast should be used during pregnancy only if clearly needed.

Lactation: Zafirlukast is excreted in human breast milk. Following repeated 40 mg twice-a-day dosing in healthy women, average steady-state concentrations of zafirlukast in breast milk were 50 ng/mL compared to 255 ng/mL in plasma. Because of the potential for tumorigenicity shown for zafirlukast in mouse and rat studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects of zafirlukast, it should not be administered to mothers who are breast-feeding.

Drug Interactions : Zafirlukast may be administered with other therapies routinely used in the management of asthma and allergy. Examples of agents which have been coadministered with zafirlukast without adverse interaction include inhaled steroids, inhaled and oral bronchodilator therapy, antihistamines and antibiotics.

Coadministration with:

1) erythromycin will result in decreased plasma levels of zafirlukast. In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg 3 times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.

2) ASA may result in increased plasma levels of zafirlukast. Coadministration of zafirlukast (40 mg/day) with ASA (650 mg 4 times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.

3) Theophylline may result in decreased plasma levels of zafirlukast, without effect on plasma theophylline levels. Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.

4) Terfenadine decreases zafirlukast AUC, but has no effect on plasma terfenadine levels. In a drug interaction study in 16 healthy male volunteers, coadministration of zafirlukast (320 mg/day), with terfenadine (60 mg twice daily) to steady-state resulted in a decrease in the mean Cmax (-66%) and AUC (-54%) of zafirlukast. No effect of zafirlukast on terfenadine plasma concentrations or ECG parameters (i.e., QTc interval) was seen. No formal drug-drug interaction studies between zafirlukast and other drugs known to be metabolized by the P450 3A4 (CYP 3A4) isoenzymes have been conducted (see Cytochrome P450 Enzyme Inhibition).

5) Warfarin increases in prothrombin time by approximately 35%. In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see Warnings). Oral contraceptives may be administered with zafirlukast without adverse interaction. In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.

Cytochrome P450 Enzyme Inhibition: Aside from warfarin and terfenadine, no formal zafirlukast drug-drug interaction studies have been conducted with other drugs known to be metabolized by cytochrome P450 isoenzymes. However, care should be exercised when zafirlukast is coadministered with metabolised drugs such as: tolbutamide, phenytoin, carbamazepine (isozyme 2C9); dihydropyridine calcium channel blockers, cyclosporin, cisapride, astemizole (isozyme CYP 3A4).

Food Interaction: Zafirlukast bioavailability may be altered when taken with a meal (see Pharmacology, Pharmacokinetics).

Adverse Effects

The safety database for zafirlukast consists of more than 4 000 healthy volunteers and patients who received zafirlukast, of which 1 723 were asthmatics enrolled in trials of 13-weeks duration or longer. A total of 671 patients received zafirlukast for 1 year or longer. The majority of the patients were 18 years of age or older; however 222 patients between the age of 12 and 18 years received zafirlukast.

Liver Enzymes: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. Most of these have been observed in asymptomatic patients at doses 4 times higher than the recommended dose and returned to the normal range after a variable period of time upon discontinuation of zafirlukast therapy. Rare cases of symptomatic hepatitis and hyperbilirubinemia, without other attributable cause, have occurred in patients who had received the recommended doses of zafirlukast (40 mg/day). In these patients, the liver enzymes returned to normal or near normal after stopping zafirlukast (See Warnings and Precautions).

Infections and Age: In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose proportional to total mg of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown.

Eosinophilic Conditions: The reduction of the oral steroid dose, in some patients on zafirlukast therapy has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. A causal relationship with zafirlukast has not been established (See Precautions). Hypersensitivity reactions, including urticaria angioedema and rashes, with or without blistering, have been reported in association with zafirlukast therapy.

Overdose

Symptoms and Treatment: No deaths occurred at oral zafirlukast doses of 2 000 mg/kg in mice (approximately 200 times the maximum recommended human daily oral dose on a mg/mbasis), 2 000 mg/kg in rats (approximately 400 times the maximum recommended human daily oral dose on a mg/mbasis), and 500 mg/kg in dogs (approximately 330 times the maximum recommended human daily oral dose on a mg/mbasis). There is no experience to date with zafirlukast overdose in humans. It is reasonable to employ the usual supportive measures in the event of an overdose; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

Dosage

Zafirlukast is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast is not a bronchodilator, and should not be used to treat acute episodes of asthma. Patients receiving zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Adults and Children Aged 12 Years and Over: The recommended dose is 20 mg, twice daily for a total daily dose of 40 mg. Since food reduces the bioavailability of zafirlukast, the drug should be taken at least 1 hour before or 2 hours after meals.

Geriatrics: The clearance of zafirlukast is reduced in elderly patients (>65 years old), such that Cmax and AUC are approximately twice those of younger adults. However, accumulation of zafirlukast is not evident in elderly patients. In clinical trials, a dose of 20 mg b.i.d. was not associated with an increase in the incidence of adverse events or withdrawals because of adverse events in elderly patients. Children: The safety and efficacy in children under 12 years has not been established.

Renal Impairment: Dosage adjustment is not required in patients with renal impairment. Hepatic Impairment: Zafirlukast is not recommended for patients with hepatic impairment, including hepatic cirrhosis. The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that Cmax and AUC are approximately 50 to 60% greater than those of normal adults.

Information for the Patient: See Blue Section – Information for the Patient Accolate”.

Supplied

Each white, round, biconvex, film-coated, intagliated tablet contains: zafirlukast 20 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, polyvidone and titanium dioxide. Calendar packs of 60. Store between 15 and 30°C.

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