Endodan

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of oxycodone and aspirin combination in the pediatric population. Because of aspirin's toxicity, use in children is not recommended. Do not give aspirin to a child who has chickenpox or flu symptoms, unless approved by a doctor. Aspirin can cause a life-threatening reaction called Reye syndrome.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oxycodone and aspirin combination in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or lung problems, which may require caution and an adjustment in the dose for patients receiving oxycodone and aspirin combination.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Defibrotide
• Dichlorphenamide
• Influenza Virus Vaccine, Live
• Ketorolac
• Nalmefene
• Naltrexone
• Safinamide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone
• Acarbose
• Aceclofenac
• Acemetacin
• Acepromazine
• Alfentanil
• Alipogene Tiparvovec
• Almotriptan
• Alprazolam
• Alteplase, Recombinant
• Alvimopan
• Amiloride
• Amineptine
• Amiodarone
• Amisulpride
• Amitriptyline
• Amitriptylinoxide
• Amobarbital
• Amoxapine
• Amphetamine
• Amprenavir
• Amtolmetin Guacil
• Anagrelide
• Anileridine
• Anisindione
• Apixaban
• Aprepitant
• Argatroban
• Aripiprazole
• Asenapine
• Atazanavir
• Baclofen
• Bendroflumethiazide
• Benperidol
• Benzphetamine
• Benzthiazide
• Betrixaban
• Bivalirudin
• Boceprevir
• Bromazepam
• Bromfenac
• Bromopride
• Brompheniramine
• Bufexamac
• Bumetanide
• Buprenorphine
• Buspirone
• Butabarbital
• Butorphanol
• Carbamazepine
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Celecoxib
• Ceritinib
• Chloral Hydrate
• Chlordiazepoxide
• Chlorothiazide
• Chlorpheniramine
• Chlorpromazine
• Chlorpropamide
• Chlorthalidone
• Chlorzoxazone
• Choline Salicylate
• Cilostazol
• Citalopram
• Clarithromycin
• Clobazam
• Clomipramine
• Clonazepam
• Clonixin
• Clopamide
• Clopidogrel
• Clorazepate
• Clozapine
• Cobicistat
• Cocaine
• Codeine
• Conivaptan
• Cyclobenzaprine
• Cyclopenthiazide
• Cyclosporine
• Dabigatran Etexilate
• Danaparoid
• Darunavir
• Desipramine
• Desirudin
• Desmopressin
• Desvenlafaxine
• Dexibuprofen
• Dexketoprofen
• Dexmedetomidine
• Dextroamphetamine
• Dextromethorphan
• Dezocine
• Diazepam
• Diazoxide
• Dibenzepin
• Dichloralphenazone
• Diclofenac
• Dicumarol
• Difenoxin
• Diflunisal
• Digoxin
• Dihydrocodeine
• Diphenhydramine
• Diphenoxylate
• Dipyrone
• Dolasetron
• Donepezil
• Dothiepin
• Doxepin
• Doxylamine
• Droperidol
• Droxicam
• Duloxetine
• Edoxaban
• Eletriptan
• Enflurane
• Enzalutamide
• Eplerenone
• Eptifibatide
• Erythromycin
• Escitalopram
• Estazolam
• Eszopiclone
• Ethacrynic Acid
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fentanyl
• Fepradinol
• Feprazone
• Feverfew
• Flibanserin
• Floctafenine
• Flufenamic Acid
• Fluoxetine
• Fluphenazine
• Flurazepam
• Flurbiprofen
• Fluspirilene
• Fluvoxamine
• Fondaparinux
• Fosaprepitant
• Fosphenytoin
• Fospropofol
• Frovatriptan
• Furazolidone
• Furosemide
• Ginkgo
• Glimepiride
• Glipizide
• Glyburide
• Gossypol
• Granisetron
• Halazepam
• Haloperidol
• Halothane
• Heparin
• Hexobarbital
• Hydrochlorothiazide
• Hydrocodone
• Hydroflumethiazide
• Hydromorphone
• Hydroxytryptophan
• Hydroxyzine
• Ibuprofen
• Idelalisib
• Imipramine
• Indapamide
• Indinavir
• Indomethacin
• Iproniazid
• Isocarboxazid
• Isoflurane
• Itraconazole
• Ketamine
• Ketazolam
• Ketobemidone
• Ketoconazole
• Ketoprofen
• Lepirudin
• Levomilnacipran
• Levorphanol
• Linezolid
• Lisdexamfetamine
• Lithium
• Lofepramine
• Lopinavir
• Lorazepam
• Lorcaserin
• Lornoxicam
• Loxapine
• Loxoprofen
• Lumacaftor
• Lumiracoxib
• Meclizine
• Meclofenamate
• Mefenamic Acid
• Melitracen
• Meloxicam
• Melperone
• Meperidine
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Metformin
• Methadone
• Methamphetamine
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrexate
• Methotrimeprazine
• Methyclothiazide
• Methylene Blue
• Methylnaltrexone
• Metolazone
• Midazolam
• Milnacipran
• Mirtazapine
• Mitotane
• Moclobemide
• Molindone
• Moricizine
• Morniflumate
• Morphine
• Morphine Sulfate Liposome
• Nabumetone
• Nalbuphine
• Nalorphine
• Naloxone
• Naproxen
• Naratriptan
• Nateglinide
• Nefazodone
• Nelfinavir
• Nepafenac
• Nialamide
• Nicomorphine
• Nicorandil
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nitrazepam
• Nitrous Oxide
• Nortriptyline
• Olanzapine
• Ondansetron
• Opipramol
• Opium
• Opium Alkaloids
• Orphenadrine
• Oxaprozin
• Oxazepam
• Oxymorphone
• Oxyphenbutazone
• Palonosetron
• Papaveretum
• Parecoxib
• Paregoric
• Paroxetine
• Pemetrexed
• Pentazocine
• Pentobarbital
• Pentosan Polysulfate Sodium
• Pentoxifylline
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenelzine
• Phenindione
• Phenobarbital
• Phenprocoumon
• Phenylbutazone
• Phenytoin
• Piketoprofen
• Pimozide
• Piperacetazine
• Pipotiazine
• Piracetam
• Piritramide
• Piroxicam
• Polythiazide
• Posaconazole
• Pralatrexate
• Pranoprofen
• Prasugrel
• Prazepam
• Primidone
• Procarbazine
• Prochlorperazine
• Proglumetacin
• Promazine
• Promethazine
• Propofol
• Propyphenazone
• Proquazone
• Protein C
• Protriptyline
• Quazepam
• Quetiapine
• Ramelteon
• Rasagiline
• Remifentanil
• Remoxipride
• Repaglinide
• Reteplase, Recombinant
• Ribociclib
• Ritonavir
• Rivaroxaban
• Rizatriptan
• Rofecoxib
• Salicylic Acid
• Salsalate
• Samidorphan
• Saquinavir
• Secobarbital
• Selegiline
• Sertindole
• Sertraline
• Sibutramine
• Sodium Oxybate
• Sodium Salicylate
• Spironolactone
• Sufentanil
• Sulindac
• Sulpiride
• Sumatriptan
• Suvorexant
• Tacrolimus
• Tapentadol
• Telaprevir
• Telithromycin
• Temazepam
• Tenoxicam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tianeptine
• Tiaprofenic Acid
• Ticagrelor
• Ticlopidine
• Tilidine
• Tirofiban
• Tizanidine
• Tolazamide
• Tolbutamide
• Tolfenamic Acid
• Tolmetin
• Tolonium Chloride
• Topiramate
• Torsemide
• Tramadol
• Tranylcypromine
• Trazodone
• Treprostinil
• Triamterene
• Triazolam
• Trichlormethiazide
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Trimipramine
• Tryptophan
• Valdecoxib
• Varicella Virus Vaccine
• Venlafaxine
• Vilazodone
• Vortioxetine
• Warfarin
• Xipamide
• Zaleplon
• Ziprasidone
• Zolmitriptan
• Zolpidem
• Zopiclone
• Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Atenolol
• Betamethasone
• Betaxolol
• Bisoprolol
• Captopril
• Carteolol
• Carvedilol
• Celiprolol
• Cortisone
• Delapril
• Dexamethasone
• Enalaprilat
• Enalapril Maleate
• Esmolol
• Imidapril
• Labetalol
• Levobunolol
• Lisinopril
• Methylprednisolone
• Metipranolol
• Metoprolol
• Miconazole
• Nadolol
• Nebivolol
• Nitroglycerin
• Oxprenolol
• Paramethasone
• Penbutolol
• Pindolol
• Practolol
• Prednisolone
• Prednisone
• Probenecid
• Propranolol
• Rifampin
• Sotalol
• St John's Wort
• Streptokinase
• Tamarind
• Temocapril
• Tenecteplase
• Timolol
• Triamcinolone
• Valproic Acid
• Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Addison disease (adrenal gland problem) or
• Alcohol abuse, or history of or
• Bleeding problems or
• Brain tumor, history of or
• Chronic obstructive pulmonary disease (COPD) or
• Cor pulmonale (serious heart condition) or
• Drug dependence, especially with narcotics, or history of or
• Gallbladder disease or gallstones or
• Head injury, history of or
• Hypothyroidism (an underactive thyroid) or
• Hypovolemia (low blood volume) or
• Kyphoscoliosis (curvature of the spine with breathing problems) or
• Peptic ulcer disease, active or history of or
• Problems with passing urine or
• Prostatic hypertrophy (enlarged prostate, BPH) or
• Vitamin K deficiency—Use with caution. May increase risk for more serious side effects.

• Hemophilia or
• Lung disease or breathing problems (eg, respiratory depression), severe or
• Stomach or bowel blockage (eg, paralytic ileus) or
• Viral infection—Should not be used in patients with these conditions.

• Hypotension (low blood pressure) or
• Pancreatitis (inflammation of the pancreas) or
• Seizures, history of—Use with caution. May make these conditions worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Each Endodan Tablet contains:

Oxycodone Hydrochloride, USP     4.8355 mg1

Aspirin, USP         325 mg

Endodan Tablets also contain the following inactive ingredients: D&C Yellow 10, FD&C Yellow 6, microcrystalline cellulose and corn starch.

The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula:

The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needle-like, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula:

Central Nervous System

Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably μ and κ) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla.

Aspirin (acetylsalicylic acid) works by inhibiting the body’s production of prostaglandins, including prostaglandins involved in inflammation. Prostaglandins cause pain sensations by stimulating muscle contractions and dilating blood vessels throughout the body. In the CNS, aspirin works on the hypothalamus heat-regulating center to reduce fever, however, other mechanisms may be involved.

Gastrointestinal Tract and Other Smooth Muscle

Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone.

Aspirin can produce gastrointestinal injury (lesions, ulcers) through a mechanism that is not yet completely understood, but may involve a reduction in eicosanoid synthesis by the gastric mucosa. Decreased production of prostaglandins may compromise the defenses of the gastric mucosa and the activity of substances involved in tissue repair and ulcer healing.

Cardiovascular System

Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating.

Platelet Aggregation

Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of prostaglandin 12 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.

Pharmacokinetics

Absorption and Distribution

The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9 ±186.6 L.

Aspirin is hydrolyzed primarily to salicylic acid in the gut wall and during first-pass metabolism through the liver. Salicylic acid is absorbed rapidly from the stomach, but most of the absorption occurs in the proximal small intestine. Following absorption, salicylate is distributed to most body tissues and fluids, including fetal tissues, breast milk, and the CNS. High concentrations are found in the liver and kidneys. Salicylate is variably bound to serum proteins, particularly albumin.

Metabolism and Elimination

A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Following a single, oral dose of oxycodone, the mean ± SD elimination half-life is 3.51 ± 1.43 hours.

The biotransformation of aspirin occurs primarily in the liver by the microsomal enzyme system. With a plasma half-life of approximately 15 minutes, aspirin is rapidly hydrolyzed to salicylate. At low doses, salicylate elimination follows first-order kinetics. The plasma half-life of salicylate is approximately 2 to 3 hours.

Approximately 10% of aspirin is excreted as unchanged salicylate in the urine. The major metabolites excreted in the urine are salicyluric acid (75%), salicyl phenolic glucuronide (10%), salicyl acyl glucuronide (5%), and gentisic and gentisuric acid (less than 1%) each. Eighty to 100% of a single dose is excreted in the urine within 24 to 72 hours.

Endodan tablets are indicated for the management of moderate to moderately severe pain.

General

Opioid analgesics should be used with caution 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.

Endodan tablets should be given with caution to patients with CNS depression, elderly or debilitated patients, patients with severe impairment of hepatic, pulmonary, or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis with respiratory depression, myxedema, and toxic psychosis.

Endodan tablets 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.

Following administration of Endodan tablets, anaphylactic reactions have been reported in patients with a known hypersensitivity to codeine, a compound with a structure similar to morphine and oxycodone. The frequency of this possible cross-sensitivity is unknown.

Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.

Hemorrhage

Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities.

Pregnancy

Aspirin can cause fetal harm when administered to a pregnant woman. Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus, resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. The use of aspirin during pregnancy especially in the third trimester should be avoided. If Endodan tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Renal Failure

Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

Hepatic Insufficiency

Avoid aspirin in patients with severe hepatic insufficiency.

Interactions with Other CNS Depressants

Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with Endodan tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) 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 Postoperative Use

Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative 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, respiratory rate, or heart rate.

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

Information for Patients/Caregivers

The following information should be provided to patients receiving Endodan tablets by their physician, nurse, pharmacist, or caregiver:

1. Patients should be aware that Endodan tablets contain oxycodone, which is a morphine-like substance.
2. Patients should be instructed to keep Endodan tablets in a secure place out of the reach of children. In the case of accidental ingestions, emergency medical care should be sought immediately.
3. When Endodan tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.
4. Patients should be advised not to adjust the medication dose themselves. Instead, they must consult with their prescribing physician.
5. Patients should be advised that Endodan 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 Endodan tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician. When co-administered with another CNS depressant, Endodan tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death.
7. The safe use of Endodan tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking Endodan tablets.
8. Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue Endodan tablets because of the potential for serious adverse reactions to nursing infants.
9. Patients who are treated with Endodan tablets for more than a few weeks should be advised not to abruptly discontinue the medication. Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication.
10. Patients should be advised that Endodan 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.
11. Patients should be advised that Endodan tablets may cause or worsen constipation. They should discuss any past history of constipation with their prescribing physician so a management plan may be initiated.

Laboratory Tests

Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure.

Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative.

Drug/Drug Interactions with Oxycodone

Opioid analgesics may enhance the neuromuscular-blocking action of skeletal muscle relaxants and produce an increase in the degree of respiratory depression.

Patients receiving CNS depressants such as other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, centrally-acting anti-emetics, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with Endodan tablets may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, naltrexone, and butorphanol) should be administered with caution to a patient who has received or is receiving a pure opioid agonist such as oxycodone. These agonist/antagonist analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms.

Drug/Drug Interactions with Aspirin

Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway.

Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.

Anticoagulant Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.

Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention.

Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance.

Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent use of aspirin with other NSAID's should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance.

Oral Hypoglycemics Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia.

Uricosuric Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone.

Drug/Laboratory Test Interactions

Depending on the sensitivity/specificity and the test methodology, the individual components of Endodan tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used.

Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Animal studies to evaluate the carcinogenic potential of oxycodone and aspirin have not been performed.

Mutagenesis

The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts.

Fertility

Animal studies to evaluate the effects of oxycodone on fertility have not been performed. Aspirin has been shown to inhibit ovulation in rats.

Pregnancy

Oxycodone: Pregnancy Category B

Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic.

Aspirin: Pregnancy Category D (see PRECAUTIONS)

Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided.

Safe use of Endodan (Oxycodone and Aspirin Tablets, USP) in pregnancy has not been established relative to possible adverse effects on fetal development. Therefore, Endodan tablets should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards.

Opioids can cross the placental barrier and have the potential to cause neonatal respiratory depression. Opioid use during pregnancy may result in a physically drug-dependent fetus. After birth, the neonate may suffer severe withdrawal symptoms. Aspirin may produce anemia, ante- or postpartum hemorrhage, prolonged gestation and labor, and oligohydramnios.

Labor and Delivery

Endodan tablets are not recommended for use in women during and immediately prior to labor and delivery due to its potential effects on respiratory function in the newborn. Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported.

Nursing Mothers

Ordinarily, nursing should not be undertaken while a patient is receiving Endodan tablets because of the possibility of sedation and/or respiratory depression in the infant. Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product. Salicylic acid has also been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome caused by salicylate in breast milk is unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the potential benefits to the woman and the possible hazards to the nursing infant.

Pediatric Use

Endodan tablets should not be administered to pediatric patients. Reye Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease.

Geriatric Use

Special precaution should be given when determining the dosing amount and frequency of Endodan tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients.

Hepatic Impairment

In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment.

Renal Impairment

In a study of patients with end stage renal impairment, mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment.

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Endodan tablets are given orally.

The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets.

Cessation of Therapy

In patients treated with Endodan tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

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

Drug addiction is defined as an abnormal, compulsive use, use for non-medical purposes of a substance despite physical, psychological, occupational or interpersonal difficulties resulting from such use, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Opioid addiction is relatively rare in patients with chronic pain but may be more common in individuals who have a past history of alcohol or substance abuse or dependence. Pseudoaddiction refers to pain relief seeking behavior of patients whose pain is poorly managed. It is considered an iatrogenic effect of ineffective pain management. The health care provider must assess continuously the psychological and clinical condition of a pain patient in order to distinguish addiction from pseudoaddiction and thus, be able to treat the pain adequately.

Physical dependence on a prescribed medication does not signify addiction. Physical dependence involves the occurrence of a withdrawal syndrome when there is sudden reduction or cessation in drug use or if an opiate antagonist is administered. Physical dependence can be detected after a few days of opioid therapy. However, clinically significant physical dependence is only seen after several weeks of relatively high dosage therapy. In this case, abrupt discontinuation of the opioid may result in a withdrawal syndrome. If the discontinuation of opioids is therapeutically indicated, gradual tapering of the drug over a 2-week period will prevent withdrawal symptoms. The severity of the withdrawal syndrome depends primarily on the daily dosage of the opioid, the duration of therapy and medical status of the individual.

The withdrawal syndrome of oxycodone is similar to that of morphine. This syndrome is characterized by yawning, anxiety, increased heart rate and blood pressure, restlessness, nervousness, muscle aches, tremor, irritability, chills alternating with hot flashes, salivation, anorexia, severe sneezing, lacrimation, rhinorrhea, dilated pupils, diaphoresis, piloerection, nausea, vomiting, abdominal cramps, diarrhea and insomnia, and pronounced weakness and depression.

“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, like other opioids, has 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.

Like other opioid medications, Endodan tablets are subject to the Federal Controlled Substances Act. After chronic use, Endodan tablets should not be discontinued abruptly when it is thought that the patient has become physically dependent on oxycodone.

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.

Applies to aspirin / oxycodone: oral tablet

Along with its needed effects, aspirin / oxycodone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking aspirin / oxycodone:

• Abdominal pain, cramping, or tenderness
• agitation
• bleeding gums
• bloating
• blood in the urine or stools
• bloody, black, or tarry stools
• blue lips, fingernails, or skin
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in consciousness or confusion
• chest pain or discomfort
• chills
• clay-colored stools
• constipation
• convulsions
• coughing or vomiting blood
• dark-colored urine
• decrease in urine volume or frequency
• decreased appetite
• depression
• difficult, fast, noisy breathing, sometimes with wheezing
• difficulty in passing urine (dribbling)
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drowsiness
• dry mouth
• fainting
• fast, slow, irregular, pounding, or racing heartbeat or pulse
• feeling of hostility or irritability
• feeling of warmth
• feeling that something terrible will happen
• fever
• headache, sudden, severe
• heartburn
• hives, itching, or skin rash
• increased menstrual flow or vaginal bleeding
• increased sweating
• indigestion
• irregular, fast, slow, or shallow breathing
• large, flat, blue or purplish patches in the skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of consciousness
• muscle cramping, weakness, or tremors
• muscle pain or stiffness
• nausea or vomiting
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red or purple spots on the skin
• prolonged bleeding from cuts
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• red or black, tarry stools or dark urine
• restlessness
• shivering
• sleepiness
• sunken eyes
• sweating
• swelling of face, ankles, hands, feet, or lower legs
• thirst
• tightness in the chest
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of material that looks like coffee grounds, severe and continuing
• weak or feeble pulse
• weakness or heaviness of the legs
• weight gain
• wrinkled skin
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking aspirin / oxycodone:

• Continuing ringing or buzzing or other unexplained noise in the ears
• decreased awareness or responsiveness
• diarrhea
• drowsiness
• enlarged pupils
• extremely high fever or body temperature
• fast, weak heartbeat
• hearing loss
• increase in heart rate
• restlessness
• severe sleepiness

Some side effects of aspirin / oxycodone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Relaxed and calm feeling
• sleepiness

• Belching
• bloated, full feeling
• blurred or loss of vision
• change in color perception
• cold sweats
• constricted, pinpoint, or small pupils (black part of the eye)
• cool, pale skin
• double vision
• excess air or gas in the stomach
• false or unusual sense of well-being
• flushed, dry skin
• fruit-like breath odor
• halos around lights
• increased hunger or thirst
• increased urination
• lack or loss of strength
• night blindness
• nightmares
• overbright appearance of lights
• red eyes
• redness of the skin
• seeing, hearing, or feeling things that are not there
• shakiness
• sleepiness or unusual drowsiness
• slurred speech
• trouble sleeping
• tunnel vision
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• weight loss

Applies to aspirin / oxycodone: oral tablet

General

The most commonly reported adverse events have included lightheadedness, dizziness, drowsiness, sedation, nausea, and vomiting.[Ref]

Gastrointestinal

Oxycodone-Aspirin:
Frequency not reported: Nausea, vomiting, constipation
Postmarketing reports: Hemorrhagic gastric/duodenal ulcer, gastric/peptic ulcer, dyspepsia, abdominal pain, diarrhea, eructation, dry mouth, gastrointestinal bleeding, intestinal perforation, pancreatitis, intestinal obstruction, ileus, thirst, aspiration

Aspirin:
Frequency not reported: Anorexia[Ref]

Nervous system

Frequency not reported: Lightheadedness, dizziness, drowsiness, sedation
Postmarketing reports: Stupor, paresthesia, cerebral edema, coma, subdural or intracranial hemorrhage, seizures

Opioids:
Postmarketing reports: Serotonin syndrome[Ref]

Renal

Postmarketing reports: Renal insufficiency and failure[Ref]

Hematologic

Oxycodone-aspirin:
Postmarketing reports: Unspecified hemorrhage, purpura, reticulocytosis, prolongation of prothrombin time, disseminated intravascular coagulation, ecchymosis, thrombocytopenia

Aspirin:
Frequency not reported: Leukopenia, thrombocytopenia, purpura, decreased iron concentration, shortened erythrocyte survival time[Ref]

Hypersensitivity

Postmarketing reports: Anaphylaxis, allergic reaction, angioedema[Ref]

Cardiovascular

Frequency not reported: Hypotension
Postmarketing reports: Tachycardia, dysrhythmias, orthostatic hypotension, bradycardia, palpitations[Ref]

Metabolic

Postmarketing reports: Hypoglycemia, hyperglycemia, acidosis, alkalosis, dehydration, hyperkalemia[Ref]

Other

Postmarketing reports: Malaise, asthenia, hypothermia, accidental overdose, non-accidental overdose, hearing loss, tinnitus[Ref]

Hepatic

Oxycodone-aspirin:
Postmarketing reports: Transient elevations of hepatic enzymes, hepatitis, Reye syndrome

Aspirin:
Frequency not reported: Reversible hepatotoxicity[Ref]

Psychiatric

Frequency not reported: Euphoria, dysphoria
Postmarketing reports: Agitation, confusion, anxiety, mental impairment, drug dependence, drug abuse, depression, nervousness, hallucination[Ref]

Dermatologic

Frequency not reported: Pruritus
Postmarketing reports: Urticaria, rash, flushing, increased sweating[Ref]

Musculoskeletal

Postmarketing reports: Rhabdomyolysis

Ocular

Postmarketing reports: Miosis, visual disturbances, red eye

Genitourinary

Frequency not reported: Urinary retention, interstitial nephritis, proteinuria

Respiratory

Frequency not reported: Apnea, respiratory arrest, respiratory depression
Postmarketing reports: Bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, hypoventilation, laryngeal edema

Endocrine

Adrenal insufficiency and androgen deficiency have been reported with opioid use, most often with chronic use.

Opioids:
Postmarketing reports: Adrenal insufficiency, androgen deficiency

Some side effects of Endodan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Each ENDODAN Tablet contains:

Oxycodone Hydrochloride, USP 4.8355 mg 1

Aspirin, USP 325 mg

ENDODAN Tablets also contain the following inactive ingredients: D and C Yellow 10, FD and C Yellow 6, microcrystalline cellulose and corn starch.

The oxycodone hydrochloride component is Morphinan-6-one, 4,5-epoxy-14-hydroxy-3-methoxy-17- methyl-, hydrochloride, (5a)-., a white to off-white, hygroscopic crystals or powder, odorless, soluble in water; slightly soluble in alcohol and is represented by the following structural formula:

The aspirin component is 2-(acetyloxy)-, Benzoic acid, a white crystal, commonly tabular or needlelike, or white, crystalline powder. Is odorless or has a faint odor. Is stable in dry air; in moist air it gradually hydrolyzes to salicylic and acetic acids. Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether and is represented by the following structural formula:

1 4.8355 mg oxycodone HCl is equivalent to 4.3346 mg of oxycodone as the free base.