Duratuss DM 12 Suspension

Pronunciation: DEX-troe-meth-OR-fan/gwye-FEN-e-sin
Generic Name: Dextromethorphan/Guaifenesin
Brand Name: Duratuss DM 12

Duratuss DM 12 Suspension is used for:

Temporarily relieving cough due to the common cold, upper respiratory tract infections, sinus inflammation, sore throat, or bronchitis.

Duratuss DM 12 Suspension is a combination of an expectorant (guaifenesin) and a cough suppressant (dextromethorphan). It works by loosening mucus and lung secretions in the chest and making coughs more productive.

Do NOT use Duratuss DM 12 Suspension if:

• you are allergic to any ingredient in Duratuss DM 12 Suspension


• you are taking or have taken a monoamine oxidase inhibitor (MAOI) (eg, selegiline) within the last 14 days


• you are taking a selective serotonin reuptake inhibitor (SSRI) (eg, fluoxetine)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Duratuss DM 12 Suspension:

Some medical conditions may interact with Duratuss DM 12 Suspension. Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have chronic cough, chronic bronchitis, or any breathing problems such as asthma, emphysema, or chronic obstructive pulmonary disease (COPD)


• if you have phenylketonuria

Some MEDICINES MAY INTERACT with Duratuss DM 12 Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

• MAOIs (eg, selegiline) and SSRIs (eg, fluoxetine) because the risk of toxic side effects may be increased by Duratuss DM 12 Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Duratuss DM 12 Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Duratuss DM 12 Suspension:

Use Duratuss DM 12 Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Duratuss DM 12 Suspension by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure this dose.


• Drinking extra fluids while you are taking Duratuss DM 12 Suspension is recommended. Check with your doctor for instructions.


• If you miss a dose of Duratuss DM 12 Suspension and you are using it regularly, use it as soon as possible. If several hours have passed or if it is nearing time for the next dose, do not double the dose to catch up, unless advised by your health care provider. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Duratuss DM 12 Suspension.

Important safety information:

• Duratuss DM 12 Suspension may cause drowsiness, dizziness, blurred vision, or lightheadedness. These effects may be worse if you take it with alcohol or certain medicines. Use Duratuss DM 12 Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• If your cough lasts for more than 1 week or comes back, or if you also have a fever, rash, or persistent headache, contact your health care provider. A persistent cough could be a sign of a serious condition.


• Some of these products contain phenylalanine. If you must have a diet that is low in phenylalanine, ask your pharmacist if it is in your product.


• Duratuss DM 12 Suspension has dextromethorphan in it. Before you start any new medicine, check the label to see if it has dextromethorphan in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Diabetes patients - Some brands of Duratuss DM 12 Suspension may contain sugar. This may affect your blood sugar level. Read the label carefully before using Duratuss DM 12 Suspension.


• Duratuss DM 12 Suspension should be used with extreme caution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Duratuss DM 12 Suspension while you are pregnant. It is not known if Duratuss DM 12 Suspension is found in breast milk. Do not breast-feed while taking Duratuss DM 12 Suspension.

Possible side effects of Duratuss DM 12 Suspension:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Dizziness; drowsiness; stomach upset.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Duratuss DM2 side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; excitement; hallucinations; slowed breathing.

Proper storage of Duratuss DM 12 Suspension:

Store Duratuss DM 12 Suspension at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Duratuss DM 12 Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Duratuss DM 12 Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Duratuss DM 12 Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Duratuss DM 12 Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Duratuss DM 12 resources

• Duratuss DM 12 Side Effects (in more detail)
• Duratuss DM 12 Use in Pregnancy & Breastfeeding
• Duratuss DM 12 Drug Interactions
• Duratuss DM 12 Support Group
• 0 Reviews for Duratuss DM2 - Add your own review/rating

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Oraqix

lidocaine and prilocaine

Dosage Form: periodontal gel
Oraqix®

(lidocaine and prilocaine periodontal gel) 2.5% / 2.5%

Local anesthetic for periodontal administration

Not for Injection

Oraqix Description

Oraqix® (lidocaine and prilocaine periodontal gel,) 2.5%/2.5% is a microemulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight. This eutectic mixture has a melting point below room temperature, therefore both local anesthetics exist as liquid oils rather than as crystals. Oraqix® contains poloxamer excipients, which show reversible temperature-dependent gelation. Together with the lidocaine-prilocaine 1:1 mixture, the poloxamers form a low-viscosity fluid system at room temperature and an elastic gel in the periodontal pocket. Oraqix® is administered into periodontal pockets, by means of the supplied special applicator. Gelation occurs at body temperature, followed by release of the local anesthetics, lidocaine and prilocaine. The Oraqix® single-use glass cartridges deliver up to 1.7g(1.7mL) of gel (42.5 mg of lidocaine and 42.5 mg of prilocaine). Prilocaine base and lidocaine base are both relatively hydrophilic amino-amides.

STRUCTURAL FORMULAS

Lidocaine is chemically designated as 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide and has an octanol:water partition ratio of 43 at pH 7.4. The pKa of lidocaine is 7.86. Prilocaine is chemically designated as N-(2-methylphenyl)-2 (propylamino)-propanamide and has an octanol:water partition ratio of 25 at pH 7.4. The pKa of prilocaine is 7.89.

Each gram of Oraqix® contains 25-mg lidocaine base and 25-mg prilocaine base. The gel also contains thermosetting agents (poloxamer 188 purified, poloxamer 407 purified), hydrochloric acid (pH adjustment), and purified water. The pH of Oraqix® is 7.5-8.0.

Oraqix - Clinical Pharmacology

Lidocaine and prilocaine belong to the amide class of local anesthetics. Both lidocaine and prilocaine block sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia.

Oraqix® is applied directly into periodontal pockets to provide localized anesthesia. The onset of local anesthetic effect after application of Oraqix® occurs by 30 seconds and a longer waiting time does not enhance the anesthetic affect. Anesthetic effect, as assessed by probing of pocket depths, lasted for about 20 minutes (individual overall range 14 – 31 minutes).

PHARMACOKINETICS

Absorption

Lidocaine and prilocaine are absorbed from Oraqix® via the oral mucous membranes. After a single application of 0.9–3.5 g Oraqix®, the mean (±SD) lidocaine and prilocaine Cmax values were 182 (±53) and 77 (±27) ng/mL, respectively. After a total of 8 – 8.5 g Oraqix® administered as repeated applications over 3 hours, the mean (±SD) lidocaine Cmax was 284 (±122) ng/mL, ranging between 157 and 552 ng/mL. The mean lidocaine AUC∞ was 84,000 ng∙min/mL. The mean (±SD) prilocaine Cmax was 106 (±45) ng/mL, ranging between 53 and 181 ng/mL. The mean prilocaine AUC∞ was 26,000 ng∙min/mL.

The toxicities of lidocaine and prilocaine are thought to be additive. Systemic CNS toxicity may occur over a range of plasma concentrations of local anesthetics. CNS toxicity may typically be found around 5000 ng/mL of lidocaine, however a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL. Pharmacological thresholds for prilocaine are poorly defined.

The median Tmax of lidocaine and prilocaine was 30 minutes, ranging between 20 and 40 min., after the start of a single application of 0.9 to 3.5 g Oraqix®, and 200 minutes, ranging between 120 and 200 min., after a cumulative dose of 8.5g Oraqix® administered as repeated applications over 3 hours.

Distribution

Lidocaine and prilocaine have an intermediate degree of plasma protein binding, mainly to 1-acid glycoprotein, with a protein binding of 70% and 40%, respectively. When administered intravenously, the mean volume of distribution (for 60-kg person) at steady state for lidocaine and prilocaine were 90 L and 156 L, respectively. Oraqix® is not intended for intravenous administration. Both lidocaine and prilocaine cross the placental and blood brain barriers, presumably by passive diffusion.

Metabolism

Lidocaine and prilocaine are mainly metabolized in the liver. Prilocaine and lidocaine are not metabolized by plasma esterases.

The main metabolism of lidocaine is through N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), which is mainly mediated by CYP3A4. These metabolites are hydrolyzed to 2,6-xylidine, which is converted to 4-hydroxy-2,6-xylidine (mediated by CYP2A6), the major urinary metabolite in man. After a total of 8-8.5 g Oraqix® administered as repeated applications over 3 hours, the mean (+SD) 2,6-xylidine Cmax was 18 (+8.4) ng/mL ranging between 8 and 32 ng/mL. The mean 2,6-xylidine AUC∞ was 9800 ng.min/mL (±6370), ranging between 3480-24,580 ng/min/mL). MEGX has an antiarrhythmic and convulsant activity similar to that of lidocaine and a somewhat longer half-life. GX has a weak antiarrhythmic effect but lacks convulsant activity and has a half-life of about 10 h.

Prilocaine is split at the amide linkage to o-toluidine, which is converted further to 4- and 6- hydroxytoluidine. The prilocaine metabolite o-toluidine and the hydroxylated metabolites of o-toluidine are excreted mainly in the urine. o-Toluidine has been shown to be carcinogenic in several animal models. After a total of 8 – 8.5 g Oraqix® was administered as repeated applications over 3 hours, the mean (±SD) o-toluidine Cmax was 25 (±11) ng/mL ranging between 13 and 44 ng/mL. The mean o-toluidine AUC∞ was 9200 ng∙min/mL. The median Tmax was 220 minutes, ranging between 90 and 240 min. In addition, o-Toluidine can cause the formation of methemoglobin (metHb) following treatment with prilocaine. Individual maximum blood concentrations of metHb increased from 0 - 1.1% up to 0.8 – 1.7% following administration of the maximum recommended dose of 8.5 g Oraqix® administrated as repeated applications over 3 hours. The Tmax of metHb ranged from 1 to 4 hours. Normally, <1 % of the total hemoglobin is in the form of metHb.(see OVERDOSAGE). Patients with glucose-6-phosphate dehydrogenase deficiencies, and patients taking oxidizing drugs such as antimalarials and sulfonamides are more susceptible to drug-induced methemoglobinemia. (See WARNINGS)

Elimination

Lidocaine and prilocaine have systemic clearances of 0.95 and 2.37 L/min, respectively, after intravenous administration as single agents. The terminal half-life of both drugs after intravenous administration as single agents is 1.6 h. Oraqix® is not intended for intravenous administration.

However, after application of Oraqix® to the periodontal pockets the mean (±SD) terminal lidocaine half-life was 3.6 (±1.3) hours, ranging between 2.2 and 6.5 h. The mean (±SD) terminal prilocaine half-life was 2.8 (±1.0) hours, ranging between 2.0 to 5.7 h. For the metabolite o-toluidine the mean terminal half-life was 4.0 (±1.1) hours, ranging between 2.0 and 5.7 hours. For the metabolite 2,6-xylidine the mean terminal half-life was 8.0 (±4.0) hours, ranging between 3.7 and 18.3 hours.

Linearity

The increase in Cmax of both lidocaine and prilocaine is proportional (or less than proportional) to the dose after single application of Oraqix®. The Cmax after a cumulative dose of 8.5 g Oraqix® administered as repeated applications over 3 hours, (i.e. the highest recommended dose, corresponding to 212.5 mg each of lidocaine and prilocaine base), is lower than that extrapolated from the proportional increase in plasma concentrations at lower doses.

Pediatrics

The pharmacokinetics of lidocaine and prilocaine after Oraqix® administration have not been studied in pediatric patients.

Geriatrics

The pharmacokinetics of lidocaine and prilocaine after Oraqix® administration have not been studied in geriatric patients.

However, intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies in the intravenous pharmacokinetics of prilocaine in elderly patients have been performed.

Special populations

No pharmacokinetic studies were conducted to specifically address special populations. Renal Impairment. Lidocaine and prilocaine and their metabolites are known to be excreted by the kidney, and the metabolites may accumulate in patients with impaired renal function. Hepatic Impairment: The half-life of lidocaine may be prolonged two-fold or more in patients with liver dysfunction. Liver dysfunction may also alter prilocaine pharmacokinetics. Because of their inability to metabolize local anesthetics normally, patients with severe hepatic disease, are at a greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

Clinical Studies

A total of 337 patients (146 men and 191 women; 169 Oraqix® and 168 placebo) were studied in three randomized, double-blind, placebo-controlled trials. Subjects received a median dose of approximately 1 cartridge (1.7g gel), ranging from ¼ - 2½ cartridges per quadrant treated. The primary objective of these clinical studies was to estimate the analgesic effect of Oraqix® by asking subjects to rate their pain on a continuous visual analog scale (VAS) from 0 (no pain) to 100 mm (worst pain imaginable). Patients were asked to report overall procedural pain 5 minutes following manual scaling and/or root planing (SRP) in a single quadrant that had been pre-treated with Oraqix® or placebo (vehicle only, without lidocaine or prilocaine). In all three studies, subjects who were given Oraqix® or placebo (vehicle only, without lidocaine or prilocaine). In all three studies, subjects who were given Oraqix® reported less pain during the procedure than those given placebo. Study B3 recruited patients with a known sensitivity to mechanical probing of dental pockets, whereas in studies B1 and B2, this was not a requirement. Results of B1, B2 and B3 are summarized below.

Visual Analog Pain Scale (100 mm scale)

Visual Analog Pain Scale

Study (No. of patients)	Oraqix® Median VAS	Placebo Median VAS
* p<0.05
B1 (n=122)*	7	17
B2 (n=130)*	5	13
B3 (n=85)*	11	27

A secondary objective was to compare individual patient estimates of pain on a 5-step categorical Verbal Rating Scale (VRS) which included the following categories: no pain, mild pain, moderate pain, severe pain, and very severe pain. The results of those who reported no pain or mild pain are shown in the test table.

Verbal Rating Scale

Numger of Patients Reporting "no pain" or "mild pain" during SRP

Study (No.of Patients)	Oraqix®	Placebo
* p<0.05 in the statistical test of the full five categorical scale
B1 (n=122)*	57 (90%)	38 (64%)
B2 (n=130)*	49 (78%)	51 (76%)
B3 (n=85)*	30 (70%)	20 (48%)

Indications and Usage for Oraqix

Oraqix® is indicated for adults who require localized anesthesia in periodontal pockets during scaling and/or root planing.

Contraindications

Oraqix® is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any other component of the product.

Warnings

Prilocaine can cause elevated methemoglobin levels particularly in conjunction with methemoglobin-inducing agents. Methemoglobinemia has also been reported in a few cases in association with lidocaine treatment. Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Oraqix® should not be used iin those patients with congenital or idiopathic methemoglobinemia and in infants under the age of twelve months who are receiving treatment with methemoglobin-inducing agents. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia are characterized by a slate grey cyanosis seen in, e.g., buccal mucous membranes, lips and nail beds. In severe cases symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if metHb-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level measured with co-oximetry. Normally, metHb levels are <1%, and cyanosis may not be evident until a level of at least 10% is present. The development of methemoglobinemia is generally dose related. The individual maximum level of metHb in blood ranged from 0.8% to 1.7% following administration of the maximum dose of 8.5 g Oraqix®.

Management of Methemoglobinemia

Clinically significant symptoms of methemoglobinemia should be treated with a standard clinical regimen such as a slow intravenous infection of methylene blue at a dosage of 1-2 mg/kg given over a five minute period.

Patients taking drugs associated with drug-induced methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine are also at greater risk for developing methemoglobinemia. Treatment with Oraqix® should be avoided in patients with any of the above conditions or with a previous history of problems in connection with prilocaine treatment.

Precautions

General

DO NOT INJECT

Oraqix® should not be used with standard dental syringes. Only use these product with the Oraqix® Dispenser, which is available from DENTSPLY Pharmaceutical.

Allergic and anaphylactic reactions associated with lidocaine or prilocaine can occur. These reactions may be characterized by urticaria, angioedema, bronchospasm, and shock. If these reactions occur they should be managed by conventional means.

Oraqix® coming in contact with the eye should be avoided because animal studies have demonstrated severe eye irritation. A loss of protective reflexes may allow corneal irritation and potential abrasion. If eye contact occurs, immediately rinse the eye with water or saline and protect it until normal sensation returns. In addition, the patient should be evaluated by an ophthalmologist, as indicated.

Patients allergic to paraminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine and/or prilocaine. However, Oraqix® should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain.

Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

Information for Patients

Patients should be cautioned to avoid injury to the treated area, or exposure to extreme hot or cold temperatures, until complete sensation has returned.

Drug Interactions

Oraqix® should be used with caution in combination with dental injection anesthesia, other local anesthetics, or agents structurally related to local anesthetics, e.g., Class 1 antiarrhythmics such as tocainide and mexiletine, as the toxic effects of these drugs are likely to be additive and potentially synergistic. Patients taking drugs associated with drug-induced methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine are also at greater risk for developing methemoglobinemia. (See OVERDOSAGE).

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or prilocaine. Chronic oral toxicity studies of o-toluidine, a metabolite of prilocaine, have shown that this compound is a carcinogen in both mice and rats. The tumors associated with o-toluidine included hepatocarcinomas/ adenomas in female mice, multiple occurrences of hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in both sexes of rats, subcutaneous fibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland fibroadenomas/adenomas in female rats. These findings were observed at the lowest tested dose of 150 mg/kg/day or greater over two years (estimated daily exposures in mice and rats were approximately 6 and 12 times, respectively, the estimated exposure to o-toluidine at the maximum recommended human dose of 8.5g of Oraqix® gel on a mg/m2 basis). Thus, the no effect dose is less than 6 to 12 times the estimated exposure to o-toluidine at the maximum recommended human dose, assuming 100% bioavailialbility of prilocaine from the Oraqix® gel. Complete conversion of prilocaine to its metabolite o-toluidine on a molar basis is assumed. This gives a conversion on a weight basis of about 50% for prilocaine base (dependent on the molecular weights, i.e. 220 for prilocaine base and 107 for o-toluidine).

Mutagenesis

The mutagenic potentials of lidocaine and prilocaine have been tested in the Ames Salmonella reverse mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus assay. There was no indication of any mutagenic effects for either compound in these studies.

o-Toluidine, metabolite of prilocaine, was positive in Escherichia coli DNA repair and phage-induction assays. Urine concentrates from rats treated orally with 300 mg/kg o-toluidine were mutagenic to Salmonella typhimurium in the presence of metabolic activation. Several other tests on o-toluidine, including reverse mutations in five different Salmonella typhimurium strains with or without metabolic activation, and single strand breaks in DNA of V79 Chinese hamster cells, were negative.

Impairment of Fertility

The effect of lidocaine on fertility was examined in the rat model. Administration of 30 mg/ kg, s.c. (180 mg/m2 or 1.4 fold the maximum recommended human oral dose for one treatment session assuming 100% bioavailability of lidocaine) to the mating pair did not produce alterations in fertility or general reproductive performance of rats. There are no studies that examine the effect of lidocaine or prilocaine on sperm parameters. The effects of prilocaine on fertility was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine or prilocaine (60 mg/m2 and 180 mg/m2 on a body surface area basis, respectively up to 1.4-fold the maximum recommended exposure for a single procedure assuming 100% bioavailability of lidocaine and prilocaine). This time period encompassed 3 mating periods. There was no evidence of altered fertility.

USE IN PREGNANCY

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats with lidocaine, prilocaine and a 1:1 (weight:weight) mixture of the two compounds. There was no evidence of harm to the fetus at subcutaneous doses of up to 30 mg/kg lidocaine (estimated exposure was approximately equivalent to the expected lidocaine exposure at the maximum recommended human dose of Oraqix® (lidocaine and prilocaine periodontal gel) 2.5% / 2.5% on a mg/m2 basis). Following intramuscular prilocaine doses of up to 300 mg/kg (estimated exposure was approximately 11 times the expected prilocaine exposure at the maximum recommended human dose of Oraqix® gel on a mg/m2 basis), there was no evidence of impaired fertility or harm to the fetus. Similarly, subcutaneous administration of a lidocaine and prilocaine mixture of 40 mg/kg of each compound (estimated exposures were approximately 1.5 times the expected lidocaine and prilocaine exposures at the maximum recommended human dose of Oraqix® gel on a mg/M2 basis) produced no teratogenic, embryotoxic, or fetotoxic effects. Reproductive toxicology studies of lidocaine were also conducted in rabbits. There was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m2). Treatment of rabbits with 15 mg/kg (180 mg/m2) produced evidence of maternal toxicity and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull and sternebral defects, reduced ossification of the phalanges). The effects of lidocaine and prilocaine on post-natal development was examined in rats treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine or prilocaine (60mg/m2 and 180 mg/m2 on a body surface area basis, respectively up to 1.4-fold the maximum recommended exposure for a single procedure). This time period encompassed 3 mating periods. There was no evidence of altered post-natal development in any offspring, however, both doses of either drug significantly reduced the average number of pups per litter surviving until weaning of offspring from the first 2 mating periods. In a separate study, the effect of prilocaine on pre- and postnatal development was examined in rats treated with up to 60 mg/kg, s.c. (up to 2.8 times the maximum recommended human dose of prilocaine in Oraqix gel on a mg/m2 basis) from Day 6 of gestation to weaning. There was no evidence of altered post-natal development, viability, or reproductive capacity in any offspring. All the above calculations of exposure are assuming 100% bioavailability of lidocaine and prilocaine after Oraqix® administration. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Oraqix® should be used during pregnancy only if the benefits outweigh the risks.

Reproduction studies on the Oraqix® drug product, including the inactive ingredients, have not been conducted.

Nursing Mothers

Lidocaine and, possibly, prilocaine are excreted in breast milk. Caution should be exercised when Oraqix® is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Very young children are more susceptible to methemoglobinemia. There have been reports of clinically significant methemoglobinemia in infants and children following excessive applications of lidocaine 2.5% topical cream (See WARNINGS).

Geriatric Use

Of the total number of subjects in clinical studies of Oraqix®, 7% were aged 65 and over, while 1% were aged 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In general, dose selection for and elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

Although no major differences in adverse events between Oraqix® and placebo treated subjects were observed, all patients in the placebo controlled studies received either Oraqix® or a placebo gel (consisting of the vehicle in Oraqix® without lidocaine or prilocaine). Therefore, it is not possible to determine if adverse events in each treatment group were attributable to the inactive ingredients comprising the Oraqix® or vehicle or if adverse event rates were higher than expected background rates. Therefore, a causal relationship between the reported adverse reactions and Oraqix® could neither be established nor ruled out.

Following SRP treatment with Oraqix® in 391 patients, the most frequent adverse events were local reactions in the oral cavity (see following table). These events, which occurred in approximately 15% of patients, included pain, soreness, irritation, numbness, vesicles, ulcerations, edema and/or redness in the treated area. Of the 391 patients treated with Oraqix®, five developed ulcerative lesions and two developed vesicles of mild to moderate severity near the site of SRP. In addition, ulcerative lesions in or near the treated area were also reported for three out of 168 patients who received placebo. Other symptoms reported in more than one patient were headache, taste perversion, nausea, fatigue, flu, respiratory infection, musculoskeletal pain and accident/injury.

Table 1.Number (percent) of patients with adverse events occurring in more than one patient in any of the treatment groups. Each patient is counted only once per adverse event. The occurrence in a single patient is included in this table if the same symptom has been seen in at least one patient in another group.

System Organ Class Preferred Team	Oraqix® gel* (N = 391) n (%)	Placebo gel (N = 168) n (%)	Lidocaine injection* (N = 170) n (%)
* in a cross-over study, 170 subjects received either Oraqix® or lidocaine injection 2% in each test period † includes complaints of bad or bitter taste lasting for up to 4 hours after administration of Oraqix® ‡ i.e.,symptoms in the oral cavity § includes pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness in the treated area
Muscular-Skeletal
System Disorders
Myalgia	1(0)	2(1)
Arthralgia and/or Arthropathy	1(0)	1(1)
Central & Peripheral
Nervous System
Disorders
Headache	8(2)	3(2)	5(3)
Dizziness	1(0)	1(1)	1(1)
Special Senses Other,
Disorders
Taste Perversion†	8(2)	1(1)
Gastro-Intestinal
System Disorders
Nausea	3(1)		1(1)
Respiratory System
Disorders
Respiratory Infection	2(1)		1(1)
Rhinitis		2(1)
Body as a whole-
General Disorders
Accident and/or Injury	2(1)	2(1)
Fatigue	3(1)		2(1)
Flu-Like Disorder	2(1)
Pain (remote from application site)	1(0)	1(1)	1(1)
Application Site
Disorders‡
Anesthesia Local	2(1)
Application Site Reaction§	52(13)	20(12)

Allergic Reactions

Allergic and anaphylactic reactions associated with lidocaine or prilocaine can occur. They may be characterized by urticaria, angioedema, bronchospasm, and shock. If they occur, they should be managed by conventional means.

Overdosage

Local anesthetic toxicity emergency

Oraqix® used at the recommended doses is not likely to cause toxic plasma levels of lidocaine or prilocaine. However, if other local anesthetics are administered at the same time, e.g. topically or by injection, the toxic effects are thought to be additive and could result in an overdose with systemic toxic reactions. There is generally an increase in severity of symptoms with increasing plasma concentrations of lidocaine and/or prilocaine. Systemic CNS toxicity may occur over a range of plasma concentrations of local anesthethics. CNS toxicity may typically be found around 5000 ng/mL of lidocaine, however a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL. Pharmacological thresholds for prilocaine are poorly defined. Central nervous system (CNS) symptoms usually precede cardiovascular manifestations. The plasma level of lidocaine observed after the maximum recommended dose (5 cartridges) of Oraqix® in 11 patients exposed over 3 hours ranged from 157-552 ng/mL with a mean of 284 ng/mL ± 122 SD. The corresponding figure for prilocaine was 53-181 ng/mL with a mean of 106 ± 45 SD. (see CLINICAL PHARMACOLOGY, Absorption).

Systemic adverse effects of lidocaine and/or prilocaine are manifested by central nervous system and/or cardiovascular symptoms.

Clinical symptoms of systemic toxicity include CNS excitation and/or depression (light-headedness, hyperacusis, visual disturbances, muscular tremors, and general convulsions). Lidocaine and/or prilocaine may cause decreases in cardiac output, total peripheral resistance and mean arterial pressure. These changes may be attributable to direct depressant effects of these local anesthetic agents on the cardiovascular system. Cardiovascular manifestations may include hypotension, bradycardia, arrhythmia, and cardiovascular collapse.

Management of Local Anesthetic Emergencies

Should severe CNS or cardiovascular symptoms occur, these may be treated symptomatically by, for example, the administration of anticonvulsive drugs, respiratory support and/or cardiovascular resuscitation as necessary.

Methemoglobinemia

Prilocaine can cause elevated methemoglobinemia has also been reported in a few cases in association with lidocaine treatment. Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Very young patients, patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia are characterized by a slate grey cyanosis seen in , e.g., buccal mucous membranes, lips and nail beds. In severe cases symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if metHb-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level measured with co-oximetry. Normally, metHb levels are <1%, and cyanosis may not be evident until a level of at least 10% is present. The development of methemoglobinemia is generally dose related. The individual maximum level of metHb in blood ranged from 0.8% to 1.7% following administration of the maximum dose of 8.5 g Oraqix®.

Management of Methemoglobinemia

Clinically significant symptoms of methemoglobinemia should be treated with a standard clinical regimen such as a slow intravenous injection of methylene blue at a dosage of 1-2 mg/kg given over a five minute period.

Oraqix Dosage and Administration

Apply Oraqix® on the gingival margin around the selected teeth using the blunt-tipped applicator included in the package. Wait 30 seconds, then fill the periodontal pockets with Oraqix® using the blunt-tipped applicator until the gel becomes visible at the gingival margin. Wait another 30 seconds before starting treatment. A longer waiting time does not enhance the anesthesia. Anesthetic effect, as assessed by probing of pocket depths, has a duration of approximately 20 minutes (individual overall range 14 – 31 minutes). If the anesthesia starts to wear off, Oraqix® may be re-applied if needed. The maximum recommended dose of Oraqix® at one treatment session is 5 cartridges, i.e., 8.5g gel. Application of Oraqix® into periodontal pockets without prior application to the gingival margin was tested in one open-label study. This method of application appears to be safe; however, its efficacy has not been tested.

Typically, 1 cartridge (1.7g) or less of Oraqix® will be sufficient for one quadrant of the dentition.

When administered, Oraqix® should be a liquid. If it has formed a gel, it should be placed in a refrigerator (do not freeze) until it becomes a liquid again. When in the liquid state, the air bubble visible in the cartridge will move if the cartridge is tilted.

DO NOT INJECT

Oraqix® should not be used with standard dental anesthetic syringes. Only use this product with the Oraqix® Dispenser, which is available from DENTSPLY Pharmaceutical.

How is Oraqix Supplied

Oraqix® (lidocaine and prilocaine periodontal gel), 2.5%/2.5%, is supplied in dental cartridges that provide 1.7g gel. Individually blister-packaged cartridges of Oraqix® are distributed in a carton of 20 (NDC 66312-110-20). Each individual blister package also contains a sterile blunt-tipped applicator. Each blunt-tipped applicator is for single use only.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature.]

At temperatures below +5°C Oraqix® may become opaque. This opacity will disappear when the cartridge is warmed to room temperature.

DO NOT FREEZE. Some components of Oraqix® may precipitate if cartridges are frozen. Cartridges should not be used if they contain a precipitate.

Do not use dental cartridge warmers with Oraqix®. The heat will cause the product to gel.

Manufactured for:

DENTSPLY Pharmaceutical

570 West College Avenue

York, PA 17404

By:

Recipharm Karlskoga AB

Karlskoga

Sweden

Rev. 03/08

48 000 96 80

Oraqix™ Dispenser

Directions For Use

Consult the Oraqix Prescribing Information for complete product information. In Canada, prescribing information can be found in the Oraqix Product Monograph. In Australia, prescribing information can be found in the Oraqix Product Information. In New Zealand, prescribing information can be found in the Oraqix Data Sheet. In the US, prescribing information can be found in the Oraqix Package Insert.

Indications for Use:

The Oraqix™ Dispenser is indicated for the administration of Oraqix (lidocaine and prilocaine periodontal gel) 2.5%/2.5%.

Contraindications:

This Dispenser is contraindicated for use with all injectable local anesthetic products.

Warnings:

DO NOT INJECT Oraqix® (lidocaine and prilocaine periodontal gel) 2.5%/2.5%.

The Dispenser should never be used to inject local anesthetic. Doing so may result in inadvertent intravascular injections.

Aspiration is not possible with the Dispenser.

Precautions related to Sterilization of the Dispenser:

It is recommended to autoclave the Dispenser before first use. Only the steam autoclave cycle recommended in the step-by-step Sterilization instructions should be used. Other cycles or methods of sterilization have not been validated for effectiveness and may damage the device. It is required to allow the Dispenser to cool to room temperature after autoclaving the device. If the Dispenser is warm, Oraqix will change to the gel form and dispensing will not be possible. Although the plastic components are "heat-resistant" polymers, some discoloration of these materials will occur after repeated steam autoclave sterilization cycles. This discoloration will not affect the function of the Dispenser. If disinfectants are used, generously spray disinfectant solution on a clean towel or gauze pad and wipe the surface of the Dispenser. Do not spray directly on device surfaces. Do not immerse in disinfectant or any other solution. Prolonged use of some surface disinfectants (such as iodophor-based solutions) may cause discoloration of the plastic Dispenser components.

Adverse Reactions:

Allergy or sensitivity to the plastic or metal components of the Dispenser is possible but rare.

Note: To clearly illustrate the drawings, the blunt-tipped end of applicator cap is not shown.

Step-by-Step Instructions:

1.

Dispenser Use

1.1 Separate an individual Oraqix blister pack at the perforation and remove the lidding paper. Remove the applicator from the plastic blister tray. The applicator has a blunt-tipped end for Oraqix application and a sharp-tipped end for piercing the rubber top of the Oraqix cartridge. Break the seal and remove the plastic cover from the sharp-tipped end of the applicator. Keep hands away from the exposed sharp-tipped end of the applicator during mounting and removal to prevent accidental injuries.
1.2 Attach the sharp-tipped end of the applicator to the tip of the Dispenser (Figure 1.2).
1.3 Reset the internal ratchet mechanism before loading the first cartridge. This is accomplished by pressing the mechanism-reset button towards the back end of the body (Figure 1.3).
1.4 The air bubble present in the Oraqix cartridge allows the user to determine if the product is in a liquid or gel form. If the bubble is fixed or moves very slowly, cool the cartridge before use to bring the product back to a liquid form. The cartridge may be loaded into the tip or body of the Dispenser (Figure 1.4). Do not remove the collar from the cartridge.
1.5 Carefully assemble the body and tip of the Dispenser with the cartridge in place (Figure 1.5). Holding the Dispenser in front of you with the tip facing right, rotate the tip sleeve section away from you until locked in place.
1.6 The blunt-tipped end of the applicator may be bent to improve access to the periodontal pockets, using the cap. If a greater bend than 45° is desired, a double-bend technique is recommended (Figure 1.6).   Note: Do not bend the applicator tip more than once in the same location. Breakage may be more likely if bent at the hub.   Save the cap from the blunt-tipped end of the applicator as it will facilitate removal of the applicator from the Dispenser when treatment is complete.
1.7 Hold the Dispenser vertically and observe the transparent portion of the tip (Figure 1.7). The air bubble in the cartridge will be visible and can be removed by depressing the paddle. This will provide more consistent flow of Oraqix. A back-light may assist with this step.
1.8 Dispense Oraqix by depressing the paddle. The volume of Oraqix used per tooth is dependent on the periodontal pocket space. Consult the Oraqix (lidocaine and prilocaine periodontal gel) 2.5%/2.5% Package Insert, Data Sheet or Product Monograph/Information for specific dose information.
1.9 Oraqix is a viscous liquid. Dispensing slowly and evenly works best.
1.10   When the cartridge is nearly empty, the rubber plunger will be visible in the transparent section of the Dispenser tip.
1.11   To reload the Dispenser, first depress the reset button (see Figure 1.3). You will hear the ratchet "click" back into the reset position.
1.12   Holding the Dispenser in front of you with the tip facing right, rotate the tip sleeve section toward you to unlock the Dispenser tip.

Doksiciklin

Doksiciklin may be available in the countries listed below.

Ingredient matches for Doksiciklin

Doxycycline

Doxycycline is reported as an ingredient of Doksiciklin in the following countries:

• Bosnia & Herzegowina


• Serbia

Doxycycline hyclate (a derivative of Doxycycline) is reported as an ingredient of Doksiciklin in the following countries:

• Croatia (Hrvatska)

International Drug Name Search

Magnesium Complexe

Magnesium Complexe may be available in the countries listed below.

Ingredient matches for Magnesium Complexe

Magnesium

Magnesium mixture of several salts (a derivative of Magnesium) is reported as an ingredient of Magnesium Complexe in the following countries:

• Switzerland

International Drug Name Search

Oxycodone ER

Generic Name: oxycodone hydrochloride

Dosage Form: tablet, film coated, extended release
OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS, 80 mg CII

0033

Rx only

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

Warning

Oxycodone hydrochloride extended-release tablets are an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine.

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing oxycodone hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Oxycodone hydrochloride extended-release tablets are an extended-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.

Oxycodone hydrochloride extended-release tablets are NOT intended for use as a prn analgesic.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets ARE FOR USE IN OPIOID TOLERANT PATIENTS ONLY. This tablet strength may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE.

Oxycodone ER Description

Oxycodone Hydrochloride Extended-Release Tablets are an opioid analgesic supplied in 80 mg tablet strength for oral administration. The tablet strength describes the amount of oxycodone per tablet as the hydrochloride salt. The structural formula for oxycodone hydrochloride is as follows:

C18H21NO4•HCl M.W. 351.82

The chemical formula is 4,5-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

Oxycodone is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL). It is slightly soluble in alcohol (octanol water partition coefficient 0.7). Each tablet contains 80 mg of oxycodone hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C blue #2 indigo carmine lake, hypromellose (2208, 100M), iron oxide yellow, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide and triacetin.

Oxycodone ER - Clinical Pharmacology

Oxycodone is a pure agonist opioid whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression, as well as analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.

Central Nervous System

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Oxycodone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone hydrochloride extended-release tablets overdose (See OVERDOSAGE).

Gastrointestinal Tract and Other Smooth Muscle

Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Oxycodone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Concentration - Efficacy Relationships

Studies in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall "drug effect", analgesia and feelings of "relaxation."

As with all opioids, the minimum effective plasma concentration for analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients must be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

Concentration - Adverse Experience Relationships

Oxycodone hydrochloride extended-release tablets are associated with typical opioid-related adverse experiences. There is a general relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation is altered by the development of tolerance to opioid-related side effects, and the relationship is not clinically relevant.

As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION), because the effective analgesic dose for some patients will be too high to be tolerated by other patients.

Pharmacokinetics and Metabolism

The activity of oxycodone hydrochloride extended-release tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride extended-release tablets are designed to provide extended delivery of oxycodone over 12 hours.

Breaking, chewing or crushing oxycodone hydrochloride extended-release tablets eliminates the extended delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Oxycodone release from oxycodone hydrochloride extended-release tablets is pH independent. Oxycodone is well absorbed from oxycodone hydrochloride extended-release tablets with an oral bioavailability of 60% to 87%. The relative oral bioavailability of oxycodone hydrochloride extended-release tablets to immediate-release oral dosage forms is 100%. Upon repeated dosing in normal volunteers in pharmacokinetic studies, steady-state levels were achieved within 24 to 36 hours. Dose proportionality and/or bioavailability has been established for the 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for both peak plasma levels (Cmax) and extent of absorption (AUC). Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride extended-release tablets was 4.5 hours compared to 3.2 hours for immediate-release oxycodone.

Absorption

About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. In normal volunteers, the t½ of absorption is 0.4 hours for immediate-release oral oxycodone. In contrast, oxycodone hydrochloride extended-release tablets exhibit a biphasic absorption pattern with two apparent absorption half-times of 0.6 and 6.9 hours, which describes the initial release of oxycodone from the tablet followed by a prolonged release.

Dose proportionality has been established for the 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 1 below). Given the short half-life of elimination of oxycodone from oxycodone hydrochloride extended-release tablets, steady-state plasma concentrations of oxycodone are achieved within 24 to 36 hours of initiation of dosing with oxycodone hydrochloride extended-release tablets. In a study comparing 10 mg of oxycodone hydrochloride extended-release tablets every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two treatments were found to be equivalent for AUC and Cmax, and similar for Cmin (trough) concentrations. There was less fluctuation in plasma concentrations for the oxycodone hydrochloride extended-release tablets than for the immediate-release formulation.

Table 1: Mean [% coefficient variation]

* for single-dose AUC=AUC 0-inf; for multiple-dose AUC=AUC 0-T † data obtained while volunteers received naltrexone which can enhance absorption
Regimen	Dosage Form	AUC (ng·hr/mL)*	Cmax (ng/mL)	Tmax (hrs)	Trough Conc. (ng/mL)
Single Dose	10 mg oxycodone hydrochloride extended-release tablets	100.7 [26.6]	10.6 [20.1]	2.7 [44.1]	n.a.
	20 mg oxycodone hydrochloride extended-release tablets	207.5 [35.9]	21.4 [36.6]	3.2 [57.9]	n.a.
	40 mg oxycodone hydrochloride extended-release tablets	423.1 [33.3]	39.3 [34.0]	3.1 [77.4]	n.a.
	80 mg oxycodone hydrochloride extended-release tablets†	1085.5 [32.3]	98.5 [32.1]	2.1 [52.3]	n.a.
Multiple Dose	10 mg oxycodone hydrochloride extended-release tablets q12h	103.6 [38.6]	15.1 [31.0]	3.2 [69.5]	7.2 [48.1]
	5 mg immediate-release q6h	99.0 [36.2]	15.5 [28.8]	1.6 [49.7]	7.4 [50.9]

Table 2: Mean [% coefficient variation]

* for single-dose AUC=AUC0-inf; for multiple-dose AUC=AUC0-T † data obtained while volunteers received naltrexone which can enhance absorption
Regimen	Dosage Form	AUC4 (ng·hr/mL)*	Cmax (ng/mL)	Tmax (hrs)	Trough Conc. (ng/mL)
Single Dose	4 × 40 mg oxycodone hydrochloride extended-release tablets†	1935.3 [34.7]	152.0 [28.9]	2.56 [42.3]	n.a.
	2 × 80 mg oxycodone hydrochloride extended-release tablets†	1859.3 [30.1]	153.4 [25.1]	2.78 [69.3]	n.a.
	1 × 160 mg oxycodone hydrochloride extended-release tablets†	1856.4 [30.5]	156.4 [24.8]	2.54 [36.4]	n.a.

OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a study involving 21 normal volunteers show that oxycodone hydrochloride extended-release tablets administered per rectum resulted in an AUC 39% greater and a Cmax 9% higher than tablets administered by mouth. Therefore, there is an increased risk of adverse events with rectal administration.

Food Effects

Food has no significant effect on the extent of absorption of oxycodone from oxycodone hydrochloride extended-release tablets.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was about 45%. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk (see PRECAUTIONS).

Metabolism

Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.

The formation of oxymorphone, but not noroxycodone, is mediated by cytochrome P450 2D6 and, as such, its formation can, in theory, be affected by other drugs (see Drug-Drug Interactions).

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults.

Special Populations

Elderly

The plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects.

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Renal impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively.

This is accompanied by an increase in sedation but not by differences in respiratory rate, pupillary constriction, or several other measures of drug effect. There was an increase in t½ of elimination for oxycodone of only 1 hour (see PRECAUTIONS).

Hepatic impairment

Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, than normal subjects. AUC values are 95% and 65% higher, respectively. Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%. These differences are accompanied by increases in some, but not other, drug effects. The t½ elimination for oxycodone increased by 2.3 hours (see PRECAUTIONS).

Drug-Drug Interactions (see PRECAUTIONS)

Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone which represents less than 15% of the total administered dose. This route of elimination may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic anti-depressants). However, in a study involving 10 subjects using quinidine, a known inhibitor of cytochrome P450 2D6, the pharmacodynamic effects of oxycodone were unchanged.

Indications and Usage for Oxycodone ER

Oxycodone hydrochloride extended-release tablets are an extended-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.

Oxycodone hydrochloride extended-release tablets are NOT intended for use as a prn analgesic.

Physicians should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen to opioids in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality (formerly known as the Agency for Health Care Policy and Research), the Federation of State Medical Boards Model Guidelines, or the American Pain Society.

Oxycodone hydrochloride extended-release tablets are not indicated for pain in the immediate post-operative period (the first 12 to 24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. Oxycodone hydrochloride extended-release tablets are only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines.)

Contraindications

Oxycodone hydrochloride extended-release tablets are contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindicated. This includes patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone hydrochloride extended-release tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.

Warnings

OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR CRUSHED. TAKING BROKEN, CHEWED OR CRUSHED OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. This tablet strength may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets are for use only in opioid tolerant patients requiring daily oxycodone equivalent dosages of 160 mg or more. Care should be taken in the prescribing of this tablet strength. Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death.

Misuse, Abuse and Diversion of Opioids

Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing oxycodone hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Oxycodone hydrochloride extended-release tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Interactions with Alcohol and Drugs of Abuse

Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

DRUG ABUSE AND ADDICTION

Oxycodone hydrochloride extended-release tablets are a mu-agonist opioid with an abuse liability similar to morphine and are a Schedule II controlled substance. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone hydrochloride extended-release tablets, like other opioids, have been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Oxycodone hydrochloride extended-release tablets are intended for oral use only. Abuse of the crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Respiratory Depression

Respiratory depression is the chief hazard from oxycodone, the active ingredient in oxycodone hydrochloride extended-release tablets, as with all opioid agonists. Respiratory depression is a particular problem in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.

Oxycodone should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Head Injury

The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect

Oxycodone hydrochloride extended-release tablets may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone may produce orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Precautions

General

Opioid analgesics have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.

Use of oxycodone hydrochloride extended-release tablets is associated with increased potential risks and should be used only with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); CNS depression or coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis.

The administration of oxycodone may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Interactions with other CNS Depressants

Oxycodone hydrochloride extended-release tablets should be used with caution and started in a reduced dosage (1/3 to 1/2 of the usual dosage) in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of oxycodone hydrochloride extended-release tablets.

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients.

Ambulatory Surgery and Post-Operative Use

Oxycodone hydrochloride extended-release tablets are not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).

Oxycodone hydrochloride extended-release tablets are not indicated for pain in the immediate post-operative period (the first 12 to 24 hours following surgery) for patients not previously taking the drug, because its safety in this setting has not been established.

Oxycodone hydrochloride extended-release tablets are not indicated for pain in the post-operative period if the pain is mild or not expected to persist for an extended period of time.

Oxycodone hydrochloride extended-release tablets are only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate (see American Pain Society guidelines).

Patients who are already receiving oxycodone hydrochloride extended-release tablets as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs given, and the temporary changes in physiology caused by the surgical intervention (see DOSAGE AND ADMINISTRATION).

Oxycodone hydrochloride extended-release tablets and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving opioids. Standard supportive therapy should be implemented.

Use in Pancreatic/Biliary Tract Disease

Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level.

Tolerance and Physical Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

Information for Patients/Caregivers (see PATIENT INFORMATION at the end of the package insert)

If clinically advisable, patients receiving oxycodone hydrochloride extended-release tablets or their caregivers should be given the following information by the physician, nurse, pharmacist, or caregiver:

1. Patients should be aware that oxycodone hydrochloride extended-release tablets contain oxycodone, which is a morphine-like substance.


2. Patients should be advised that oxycodone hydrochloride extended-release tablets were designed to work properly only if swallowed whole. Oxycodone hydrochloride extended-release tablets will release all their contents at once if broken, chewed or crushed, resulting in a risk of fatal overdose.


3. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.


4. Patients should be advised not to adjust the dose of oxycodone hydrochloride extended-release tablets without consulting the prescribing professional.


5. Patients should be advised that oxycodone hydrochloride extended-release tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).


6. Patients should not combine oxycodone hydrochloride extended-release tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.


7. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.


8. Patients should be advised that oxycodone hydrochloride extended-release tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.


9. Patients should be advised that if they have been receiving treatment with oxycodone hydrochloride extended-release tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the oxycodone hydrochloride extended-release tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.


10. Patients should be instructed to keep oxycodone hydrochloride extended-release tablets in a secure place out of the reach of children. When oxycodone hydrochloride extended-release tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.

Use in Drug and Alcohol Addiction

Oxycodone hydrochloride extended-release tablets are an opioid with no approved use in the management of addictive disorders. Their proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.

Drug-Drug Interactions

Opioid analgesics, including oxycodone hydrochloride extended-release tablets, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Oxycodone is metabolized in part to oxymorphone via cytochrome P450 2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. Clinicians should be aware of this possible interaction, however.

Use with CNS Depressants

Oxycodone hydrochloride extended-release tablets, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies of oxycodone to evaluate its carcinogenic potential have not been conducted.

Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. coli test with and without metabolic activation at doses of up to 5000 mcg, chromosomal aberration test in human lymphocytes in the absence of metabolic activation at doses of up to 1500 mcg/mL and with activation 48 hours after exposure at doses of up to 5000 mcg/mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 mcg/mL). Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 mcg/mL) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 mcg/mL or greater with metabolic activation and at 400 mcg/mL or greater without metabolic activation.

Pregnancy

Teratogenic Effects–Category B: Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8 mg/kg and 125 mg/kg, respectively. These doses are 3 and 46 times a human dose of 160 mg/day, based on mg/kg basis. The results did not reveal evidence of harm to the fetus due to oxycodone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Oxycodone hydrochloride extended-release tablets are not recommended for use in women during and immediately prior to labor and delivery because oral opioids may cause respiratory depression in the newborn. Neonates whose mothers have been taking oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.

Nursing Mothers

Low concentrations of oxycodone have been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone hydrochloride extended-release tablets because of the possibility of sedation and/or respiratory depression in the infant.

Pediatric Use

Safety and effectiveness of oxycodone hydrochloride extended-release tablets have not been established in pediatric patients below the age of 18. It must be remembered that oxycodone hydrochloride extended-release tablets cannot be crushed or divided for administration.

Geriatric Use

In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone appeared to be slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% (see PHARMACOKINETICS AND METABOLISM). Of the total number of subjects (445) in clinical studies of oxycodone hydrochloride extended-release tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected side effects were seen in the elderly patients who received oxycodone hydrochloride extended-release tablets. Thus, the usual doses and dosing intervals are appropriate for these patients. As with all opioids, the starting dose should be reduced to 1/3 to 1/2 of the usual dosage in debilitated, non-tolerant patients. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.

Laboratory Monitoring

Due to the broad range of plasma concentrations seen in clinical populations, the varying degrees of pain, and the development of tolerance, plasma oxycodone measurements are usually not helpful in