Oxycodone Solution Concentrate

The 5 mg per 5 mL strength: Each 5 mL of red oxycodone hydrochloride oral solution, USP contains oxycodone hydrochloride 5 mg. The concentration of this solution is 1 mg per mL.

The 100 mg per 5 mL (20 mg per mL) strength: Each 5 mL of yellow oxycodone hydrochloride oral solution, USP contains oxycodone hydrochloride 100 mg. The concentration of this solution is 20 mg per mL.

Mechanism of Action

Oxycodone hydrochloride, an opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of oxycodone hydrochloride include drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system.

Pharmacodynamics

Oxycodone concentrations are not predictive of analgesic response, especially in patients previously treated with opioids. The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

Effects on the Central Nervous System (CNS)

The principal therapeutic action of oxycodone hydrochloride is analgesia. Although the precise mechanism of the analgesic action is unknown, specific CNS opioid receptors for endogenous compounds with oxycodone hydrochloride-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression and perception of analgesic effects. In common with other opioids, oxycodone hydrochloride causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Oxycodone and related opioids depress the cough reflex by direct effect on the cough center in the medulla.

Oxycodone causes miosis, even in total darkness.

Effects on the Gastrointestinal Tract And Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by oxycodone hydrochloride. Oxycodone hydrochloride, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla. The frequency and severity of emesis gradually diminishes with time. Oxycodone hydrochloride may cause a decrease in the secretion of hydrochloric acid in the stomach, may reduce motility, while increasing the 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. The end result may be constipation. Oxycodone hydrochloride may also cause spasm of the sphincter of Oddi and transient elevations in serum amylase.

Effects on the Cardiovascular System

In therapeutic doses, oxycodone hydrochloride, produces peripheral vasodilatation (arteriolar and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Caution should be used in hypovolemic patients, such as those suffering acute myocardial infarction, because oxycodone may cause or further aggravate their hypotension. Caution should also be used in patients with cor pulmonale who have received therapeutic doses of opioids.

Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and animal models. The clinical significance of these findings is unknown.

Pharmacokinetics

The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone.

The oral bioavailability of oxycodone is 60% to 87%. Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated parent and its metabolites. The apparent elimination half-life of oxycodone is approximately 4 hours.

Absorption

About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone.

Food Effects

When oxycodone hydrochloride capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food caused a delay in Tmax (1.00 to 3 hours). Similar effects of food are expected with the oral solution.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk.

Metabolism

Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. 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.

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.

Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours.

Special Populations

Elderly: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

Gender: Information obtained from oxycodone tablets support the lack of gender effect on the pharmacokinetics of oxycodone.

Renal Impairment: Information obtained from oxycodone tablets indicate that patients with renal impairment (defined as creatinine clearance <60 mL/min) had higher plasma concentrations of oxycodone than subjects with normal renal function.

Hepatic Impairment: Since oxycodone is extensively metabolized, its clearance may be decreased in patients with hepatic impairment.

Drug-Drug Interactions

CYP3A4 Inhibitors

CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the coadministration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively.

CYP3A4 Inducers

A published study showed that the coadministration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively.

CYP2D6 Inhibitors

Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Impairment of Fertility

The potential effects of oxycodone on male and female fertility have not been evaluated.

Oxycodone hydrochloride oral solution, USP 100 mg per 5 mL (20 mg per mL) is a yellow solution available in one strength as follows:

100 mg per 5 mL (20 mg per mL) oral solution

NDC 68094-801-58
0.5 mL per unit dose syringe
Fifty (50) syringes per shipper

NDC 68094-310-58
1 mL per unit dose syringe
Fifty (50) syringes per shipper

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]

PROTECT from MOISTURE AND LIGHT.

Handling

All opioids, including oxycodone hydrochloride, are liable to diversion and misuse both by the general public and healthcare workers and should be handled accordingly.

DEA Order Form Required

See Medication Guide

Provide the following information to patients receiving oxycodone hydrochloride or their caregivers:

• Advise patients that oxycodone hydrochloride is a narcotic pain reliever, and should be taken only as directed.
• Advise patients how to take the correct dose of oxycodone hydrochloride oral solution.
• Advise patients whenever the prescribed concentration is changed to avoid dosing errors which could result in accidental overdose and death.
• Advise patients that the 100 mg per 5 mL (20 mg per mL) formulation is only for patients who are already receiving opioid-therapy and have demonstrated opioid-tolerance and that sharing this medication can result in fatal overdose and death, particularly in persons who have not had previous exposure to opioids.
• Advise patients not to adjust the dose of oxycodone hydrochloride without consulting with a physician or other healthcare professional.
• Advise patients that oxycodone hydrochloride may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Advise patients started on oxycodone hydrochloride or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely affected.
• Advise patients that oxycodone hydrochloride will add to the effect of alcohol and other CNS depressants (such as antihistamines, sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and monoamine oxidase [MAO] inhibitors).
• Instruct patients not to combine oxycodone hydrochloride with central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, and not to combine with alcohol because dangerous additive effects may occur, resulting in serious injury or death.
• Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiating or continuing therapy with oxycodone hydrochloride.
• Advise patients that safe use in pregnancy has not been established and that prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence, and neonatal withdrawal may occur.
• If patients have been receiving treatment with oxycodone hydrochloride for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication.
• Advise patients that oxycodone hydrochloride is a potential drug of abuse. They must protect it from theft. It should never be given to anyone other than the individual for whom it was prescribed.
• Instruct patients to keep oxycodone hydrochloride in a secure place out of the reach of children. When oxycodone hydrochloride is no longer needed, the unused solution should be destroyed by flushing down the toilet.
• Advise patients taking oxycodone hydrochloride of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.
• Advise patients of the most common adverse events that may occur while taking oxycodone hydrochloride: constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.
• Advise patients to call 911 or the local Poison Control center, and get emergency help immediately if they take more oxycodone than prescribed, or overdose.
• Advise patients, that if they miss a dose, to take the missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to their regular dosing schedule. Do not take two doses at once unless instructed by their doctor.

Manufactured by:
Mayne Pharma
Greenville, NC 27834
1-844-825-8500

Packaged by:
Precision Dose, Inc.
South Beloit, IL 61080

LI1030

Rev. 02/16

IMPORTANT: Keep oxycodone hydrochloride oral solution in a safe place away from children. Accidental use by a child is a medical emergency and can cause death. If a child accidentally takes oxycodone hydrochloride oral solution, get emergency help right away.

Read the Medication Guide that comes with oxycodone hydrochloride oral solution before you start taking it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about oxycodone hydrochloride oral solution?

Oxycodone hydrochloride oral solution can cause serious side effects, including, death.

1. Take oxycodone hydrochloride oral solution exactly as prescribed by your healthcare provider. If you take the wrong dose or strength of oxycodone hydrochloride oral solution, you could overdose and die. 2. It is especially important when you take oxycodone hydrochloride oral solution that you know exactly what dose and strength to take. 3. Oral Syringe. 4. Do not drink alcohol. Using alcohol with oxycodone hydrochloride oral solution may increase your risk of dangerous side effects, including death. 5. Opioid Tolerance. Do not take oxycodone hydrochloride oral solution, 100 mg per 5 mL (20 mg per mL), unless you are "opioid tolerant." Opioid tolerant means that you take another opioid medicine for your constant (around-the-clock) pain and your body is used to it.

What is oxycodone hydrochloride oral solution?

Oxycodone hydrochloride oral solution is in a group of drugs called narcotic pain relievers.

Oxycodone hydrochloride oral solution is only for adults who have moderate to severe pain.

• Oxycodone hydrochloride oral solution is a prescription medicine that is used to manage moderate to severe pain that is expected to last a short period of time (acute), and pain that continues around-the-clock and is expected to last for a long period of time (chronic).
• Oxycodone hydrochloride oral solution is a federally controlled substance (CII) because it is a strong opioid pain medicine that can be abused by people who abuse prescription medicines or street drugs.
• Prevent theft, misuse or abuse. Keep oxycodone hydrochloride oral solution in a safe place to keep it from being stolen. Oxycodone hydrochloride oral solution can be a target for people who misuse or abuse prescription medicines or street drugs.
• Never give oxycodone hydrochloride oral solution to anyone else, even if they have the same symptoms you have. It may harm them or even cause death.
• Selling or giving away this medicine is against the law.
• It is not known if oxycodone hydrochloride oral solution is safe and effective in children under 18 years of age.
• Oxycodone hydrochloride 100 mg per 5 mL (20 mg per mL) oral solution is only for adults with moderate to severe pain who are already using an opioid narcotic pain medicine and have been using this medicine continuously for several weeks or longer.

Who should not take oxycodone hydrochloride oral solution?

Do not take oxycodone hydrochloride oral solution if you:

• are allergic to oxycodone, oxycodone salts, or any of the ingredients in oxycodone hydrochloride oral solution.
  See the end of this Medication Guide for a complete list of ingredients in oxycodone hydrochloride oral solution.
• are having breathing problems and there is no emergency medical equipment nearby
• are having an asthma attack or have severe asthma, trouble breathing, or lung problems
• have a bowel blockage called paralytic ileus

What should I tell my healthcare provider before taking oxycodone hydrochloride oral solution?

Before taking oxycodone hydrochloride oral solution, tell your healthcare provider if you:

• have trouble breathing or lung problems
• have had a head injury
• have liver or kidney problems
• have adrenal gland problems, such as Addison's disease
• have severe scoliosis that affects your breathing
• have thyroid problems
• have problems urinating or enlargement of your prostate
• have or had convulsions or seizures
• have a past or present drinking problem or alcoholism
• have hallucinations (seeing or hearing things that are not really there) or other severe mental problems
• have constipation or other bowel problems
• have problems with your pancreas or gallbladder
• have past or present substance abuse or drug addiction
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if oxycodone hydrochloride oral solution will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
  If you take oxycodone hydrochloride oral solution regularly before your baby is born, your newborn baby may have signs of withdrawal because their body has become used to the medicine. Signs of withdrawal in a newborn baby can include:
• irritability
• vomiting
• being very active
• diarrhea or more stools than normal
• problems sleeping
• high pitched cry
• weight loss
• shaking (tremors)
  If you are taking oxycodone hydrochloride oral solution right before your baby is born, your baby could have breathing problems.
• are breastfeeding or plan to breastfeed. Some oxycodone hydrochloride oral solution passes into your breast milk. A nursing baby could become very sleepy or have difficulty breathing or feeding well. If you stop breastfeeding, your baby may have withdrawal symptoms. See the list of withdrawal symptoms above. You and your healthcare provider should decide if you will take oxycodone hydrochloride oral solution or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Sometimes the doses of medicines that you take with oxycodone hydrochloride oral solution may need to be changed if used together. Be especially careful about taking other medicines that make you sleepy such as:

• sleeping pills
• anti-anxiety medicines
• other pain medicines
• antidepressants
• anti-nausea medicines
• monoamine oxidase inhibitors (MAOIs)
• tranquilizers
• muscle relaxants
• anticholinergic medicines
• antihistamines

Ask your healthcare provider if you are not sure if your medicine is one listed above.

• Do not take other medicines while using oxycodone hydrochloride oral solution until you have talked with your healthcare provider or pharmacist. They will tell you if it is safe to take other medicines with oxycodone hydrochloride oral solution.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take oxycodone hydrochloride oral solution?

• See "What is the most important information I should know about oxycodone hydrochloride oral solution?"
• Take oxycodone hydrochloride oral solution exactly as prescribed. Do not change your dose unless your healthcare provider tells you to. Your healthcare provider may change your dose after seeing how the medicine affects you. Call your healthcare provider if your pain is not well controlled with your prescribed dose of oxycodone hydrochloride oral solution.
• Do not stop taking oxycodone hydrochloride oral solution suddenly. If you have been taking oxycodone hydrochloride oral solution for more than a few weeks, stopping it suddenly can make you sick with withdrawal symptoms (for example, nausea, vomiting, diarrhea, anxiety, and shivering). If your healthcare provider decides you no longer need oxycodone hydrochloride oral solution, ask how to slowly reduce this medicine. Do not stop taking oxycodone hydrochloride oral solution without talking to your healthcare provider.
• If you take more oxycodone than prescribed, or overdose, call your local emergency number (such as 911) or your local Poison Control Center right away or get emergency help.
• Talk with your healthcare provider regularly about your pain to see if you still need to take oxycodone.

What should I avoid while taking oxycodone hydrochloride oral solution?

• You should not drink alcohol while using oxycodone hydrochloride oral solution. Drinking alcohol with oxycodone hydrochloride oral solution may increase your risk of having dangerous side effects or death.
• Do not drive, operate heavy machinery, or do other dangerous activities, especially when you start taking oxycodone hydrochloride oral solution and when your dose is changed, until you know how oxycodone hydrochloride oral solution affects you.
  Oxycodone can make you sleepy. Ask your healthcare provider to tell you when it is okay to do these activities.

What are the possible side effects of oxycodone hydrochloride oral solution?

Oxycodone hydrochloride oral solution can cause serious side effects, including:

• See "What is the most important information I should know about oxycodone hydrochloride oral solution?"
• Oxycodone can cause serious breathing problems that can become life-threatening, especially if oxycodone hydrochloride oral solution is used the wrong way. Call your healthcare provider or get help right away if:
• your breathing slows down
• you have shallow breathing (little chest movement with breathing)
• you feel faint, dizzy, confused, or
• you have any other unusual symptoms

These can be symptoms that you have taken too much oxycodone hydrochloride oral solution (overdose) or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away.

• Oxycodone hydrochloride oral solution can cause your blood pressure to drop. This can make you feel dizzy if you get up too fast from sitting or lying down. Low blood pressure is also more likely to happen if you take other medicines that can also lower your blood pressure. Severe low blood pressure can happen if you lose blood or take certain other medicines.
• Oxycodone can cause physical dependence. Do not stop taking oxycodone or any other opioid without talking to your healthcare provider about how to slowly stop your medicine. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependence is not the same as drug addiction. Tell your healthcare provider if you have any of these symptoms of withdrawal while slowly stopping oxycodone:
• feel restless
• runny nose
• tearing eyes
• yawning
• sweating
• nausea, loss of appetite, vomiting, diarrhea, stomach-area (abdominal) cramps
• chills or hair on your arms "stand up"
• muscle aches, backache
• increase in your blood pressure, breathing faster, or your heart beats faster
• dilated pupils of your eyes
• feel irritable or anxious
• trouble sleeping
• There is a chance of abuse or addiction with oxycodone hydrochloride oral solution. The chance is higher if you are or have been addicted to or abused other medicines, street drugs, or alcohol, or if you have a history of mental problems.
• Seizures. Oxycodone hydrochloride oral solution may cause seizures or make seizures that you already have worse.

Call your healthcare provider if you have any of the symptoms listed above.

Common side effects of oxycodone hydrochloride oral solution include:

• nausea
• dizziness
• constipation
• weakness
• vomiting
• drowsiness
• headache
• sweating
• itchiness
• lightheadedness
• trouble sleeping

Constipation (not often enough or hard bowel movements) is a very common side effect of pain medicines (opioids) including oxycodone hydrochloride oral solution. Talk to your healthcare provider about dietary changes, and the use of laxatives (medicines to treat constipation) and stool softeners to prevent or treat constipation while taking oxycodone hydrochloride oral solution.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of oxycodone hydrochloride oral solution. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Mayne Pharma at 1-844-825-8500.

How should I store oxycodone hydrochloride oral solution?

• Store oxycodone hydrochloride oral solution in a dry area at room temperature 59°F to 86°F (15°C to 30°C).
• Protect oxycodone hydrochloride oral solution from moisture and light.
• After you stop taking oxycodone, flush the unused oral solution down the toilet.

Keep oxycodone hydrochloride oral solution out of the reach of children. Accidental overdose by a child is a medical emergency and can lead to death.

General information about oxycodone hydrochloride oral solution

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use oxycodone hydrochloride oral solution for a condition for which it was not prescribed.

Do not give your oxycodone hydrochloride oral solution to other people, even if they have the same symptoms you have. Selling or giving away oxycodone hydrochloride oral solution may harm others, may cause death, and is against the law.

This Medication Guide summarizes the most important information about oxycodone hydrochloride oral solution. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about oxycodone hydrochloride oral solution that is written for healthcare professionals.

For more information about oxycodone hydrochloride oral solution, call 1-844-825-8500.

What are the ingredients in oxycodone hydrochloride oral solution?

Active ingredient: oxycodone hydrochloride, USP

Inactive ingredients: 100 mg per 5 mL contains citric acid anhydrous, D&C Yellow No.10, natural/artificial berry flavor, purified water, sodium citrate dihydrate, sodium benzoate, saccharin sodium, and sorbitol.

Manufactured by:
Mayne Pharma
Greenville, NC 27834

Packaged by:
Precision Dose, Inc.
South Beloit, IL 61080

LI1030 Rev. 02/16

This Medication Guide has been approved by the U.S. Food and Drug Administration.