Prescription Drug Information: Oxycodone HCl Controlled-Release (Page 4 of 7)

Use with CNS Depressants

Oxycodone HCl Controlled-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 and Mutagenesis and 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 µg, chromosomal aberration test in human lymphocytes in the absence of metabolic activation at doses of up to 1500 µg/mL and with activation 48 hours after exposure at doses of up to 5000 µg/mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 µg/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 µg/mL) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 µg/mL or greater with metabolic activation and at 400 µg/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 HCl Controlled-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 HCl Controlled-Release Tablets because of the possibility of sedation and/or respiratory depression in the infant.

Pediatric Use

Safety and effectiveness of Oxycodone HCl Controlled-Release Tablets have not been established in pediatric patients below the age of 18. It must be remembered that Oxycodone HCl Controlled-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 HCl Controlled-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 HCl Controlled-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 clinical management. Plasma concentrations of the active drug substance may be of value in selected, unusual or complex cases.

Hepatic Impairment

A study of Oxycodone HCl Controlled-Release Tablets in patients with hepatic impairment indicates greater plasma concentrations than those with normal function. The initiation of therapy at 1/3 to 1/2 the usual doses and careful dose titration is warranted.

Renal Impairment

In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Dose initiation should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

Gender Differences

In pharmacokinetic studies, opioid-naive females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials.

ADVERSE REACTIONS

The safety of Oxycodone HCl Controlled-Release Tablets was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received Oxycodone HCl Controlled-Release Tablets in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day.

Serious adverse reactions which may be associated with Oxycodone HCl Controlled-Release Tablet therapy in clinical use are those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, and (to an even lesser degree) circulatory depression, hypotension, or shock (see OVERDOSAGE).

The non-serious adverse events seen on initiation of therapy with Oxycodone HCl Controlled-Release Tablets are typical opioid side effects. These events are dose-dependent, and their frequency depends upon the dose, the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent (>5%) include: constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, sweating, and asthenia.

In many cases the frequency of these events during initiation of therapy may be minimized by careful individualization of starting dosage, slow titration, and the avoidance of large swings in the plasma concentrations of the opioid. Many of these adverse events will cease or decrease in intensity as Oxycodone HCl Controlled-Release Tablet therapy is continued and some degree of tolerance is developed.

Clinical trials comparing Oxycodone HCl Controlled-Release Tablets with immediate-release oxycodone and placebo revealed a similar adverse event profile between Oxycodone HCl Controlled-Release Tablets and immediate-release oxycodone. The most common adverse events (>5%) reported by patients at least once during therapy were:

TABLE 3
Oxycodone HCl Controlled- Release Tablets (n=227) (%) Immediate-Release (n=225) (%) Placebo (n=45) (%)
Constipation (23) (26) (7)
Nausea (23) (27) (11)
Somnolence (23) (24) (4)
Dizziness (13) (16) (9)
Pruritus (13) (12) (2)
Vomiting (12) (14) (7)
Headache (7) (8) (7)
Dry Mouth (6) (7) (2)
Asthenia (6) (7)
Sweating (5) (6) (2)

The following adverse experiences were reported in Oxycodone HCl Controlled-Release Tablets-treated patients with an incidence between 1% and 5%. In descending order of frequency they were anorexia, nervousness, insomnia, fever, confusion, diarrhea, abdominal pain, dyspepsia, rash, anxiety, euphoria, dyspnea, postural hypotension, chills, twitching, gastritis, abnormal dreams, thought abnormalities, and hiccups.

The following adverse reactions occurred in less than 1% of patients involved in clinical trials or were reported in postmarketing experience.

Blood and lymphatic system disorders: lymphadenopathy

Cardiac disorders: palpitations (in the context of withdrawal)

Ear and labyrinth disorders: tinnitus

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Eye disorders: abnormal vision

Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, ileus, increased appetite, stomatitis

General disorders and administration site conditions: chest pain, edema, facial edema, malaise, pain, peripheral edema, thirst, withdrawal syndrome (with and without seizures)

Immune system disorders: anaphylactic or anaphylactoid reaction (symptoms of)

Infections and infestations: pharyngitis

Injury, poisoning and procedural complications: accidental injury

Investigations: hyponatremia, increased hepatic enzymes, ST depression

Metabolism and nutrition disorders: dehydration

Musculoskeletal and connective tissue disorders: neck pain

Nervous system disorders: abnormal gait, amnesia, hyperkinesia, hypertonia (muscular), hypesthesia, hypotonia, migraine, paresthesia, seizures, speech disorder, stupor, syncope, taste perversion, tremor, vertigo

Psychiatric disorders: agitation, depersonalization, depression, emotional lability, hallucination

Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention, urination impaired

Reproductive system and breast disorders: amenorrhea, decreased libido, impotence

Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration

Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis, urticaria

Vascular disorders: vasodilation

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