TARGINIQ ER (Page 11 of 11)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been conducted with
oxycodone alone or the oxycodone and naloxone combination.
Naloxone was tested in two carcinogenicity studies in rats and transgenic mice. Naloxone was not carcinogenic in a 2-year rat bioassay at doses as high as 100 mg/kg/day (24-times the maximum recommended daily dose of 40 mg naloxone/day on a mg/m2 basis).
Naloxone did not produce evidence of carcinogenic potential in the Tg.rasH2 mouse model.
Mutagenesis
Oxycodone was genotoxic
in the mouse lymphoma assay. Clastogenicity was observed with oxycodone
in the presence of metabolic activation in one chromosomal aberration
assay in human lymphocytes at concentrations greater than or equal
to 1250 mcg/mL at 24 but not 48 hours of exposure. In a second chromosomal
aberration assay with human lymphocytes, no structural clastogenicity
was observed either with or without metabolic activation; however,
in the absence of metabolic activation, oxycodone increased numerical
chromosomal aberrations (polyploidy). Oxycodone was not genotoxic
in the following assays: Ames S. typhimurium and E. coli test with and without metabolic activation at concentrations
up to 5000 µg/plate, chromosomal aberration test in human lymphocytes
(in the absence of metabolic activation) at concentrations up to 1500
µg/mL, and with activation after 48 hours of exposure at concentrations
up to 5000 µg/mL, and in the in vivo bone marrow
micronucleus assay in mice (at plasma levels up to 48 µg/mL).
Naloxone was genotoxic in the mouse lymphoma assay. Naloxone produced a non-dose-related increase in chromosomal aberrations in the presence of metabolic activation that was statistically significant at concentrations of 375 and 1500 mcg/mL but not at 750 or 3000 mcg/mL. In contrast, naloxone was not mutagenic in the S. typhimurium /E. coli bacterial mutagenicity test with or without metabolic activation nor was it genotoxic in in vivo mouse bone marrow micronucleus test at a dose of 500 mg/kg.
Impairment of Fertility
Fertility studies to evaluate the combination of oxycodone
and naloxone have not been conducted. In a study of reproductive
performance, rats were administered a once daily gavage dose of the
vehicle or oxycodone hydrochloride doses up to 8 mg/kg (equivalent
to the maximum recommended daily dose of 80 mg/day on a mg/m2 basis). Male rats were dosed for 28 days before
cohabitation with females, during the cohabitation and until necropsy
(2-3 weeks post-cohabitation). Females were dosed for 14 days before
cohabitation with males, during cohabitation and up to Gestation Day
6. Oxycodone hydrochloride did not affect reproductive function in
male or female rats.
Oral administration of naloxone to male and female rats at dosages as high as 800 mg/kg/day had no effect on fertility or general reproductive performance (approximately 192-times the maximum recommended daily dose of 40 mg naloxone/day, on a mg/m2 basis).
14 CLINICAL STUDIES
The efficacy of TARGINIQ ER was evaluated in one 12-week, randomized, double-blind, placebo-controlled clinical trial in opioid-experienced patients with uncontrolled moderate to severe chronic low back pain.
12-Week Study in Opioid-Experienced Patients with Uncontrolled Chronic Low Back PainA total of 1095 patients (mean age = 52 years [range 20-88]; 45% male and 55% female) with uncontrolled moderate to severe chronic low back pain entered an open-label, dose-titration period for up to four weeks. Patients initiated TARGINIQ ER therapy at an oxycodone dose approximately equivalent to their current therapy [see Dosage and Administration (2.1)]. The dose of TARGINIQ ER could be up-titrated to a maximum of 40/20 mg twice daily by the investigator every 1-2 days as needed based on efficacy, safety, and tolerability considerations or down-titrated at any time for safety and/or tolerability reasons. During open-label titration, subjects were allowed supplemental pain medication (immediate-release oxycodone HCl 5 mg capsules) for low back pain every 4 hours as needed up to 8 capsules per day.
Fifty-five percent (55%) of patients who entered the open-label titration period achieved adequate analgesia and tolerability on TARGINIQ ER and were then randomized to their final titrated dose of TARGINIQ ER or matching placebo for 12 weeks of double-blind treatment. Nine percent (9%) of patients discontinued from the open-label titration period due to an adverse event; 10% discontinued due to lack of a therapeutic effect, and 11% discontinued for other reasons. Sixteen (16%) percent did not qualify for randomization. During double-blind treatment, subjects were allowed one capsule of supplemental pain medication (immediate-release oxycodone HCl 5 mg capsules) for low back pain as needed, up to 2 capsules per day.
Of the 298 patients randomized to TARGINIQ ER, 73% of the patients completed the 12-week double-blind treatment on study drug. Of the 302 patients randomized to placebo, 60% of the patients completed the study. Fewer patients randomized to TARGINIQ ER discontinued due to lack of efficacy compared to placebo, 10% versus 24%. Discontinuation due to adverse events was the same for both TARGINIQ ER (8%) and placebo (8%).
Of the patients who were randomized, pain scores were similar at screening and end of the open-label titration for TARGINIQ ER and placebo subjects. The mean average pain over the last 24 hours (SE) scores were 7.0 (0.06) and 7.1 (0.06) at screening and 3.1 (0.06) and 3.1 (0.06) at pre-randomization (beginning of double-blind phase) for the TARGINIQ ER and placebo groups, respectively.
The mean score of average pain over the last 24 hours at the end of the study (Week 12/Early Termination) was statistically significantly lower in patients treated with TARGINIQ ER (SE), 3.9 (0.1), compared to patients treated with placebo (SE), 4.3 (0.1).
A plot of distribution of responders based on pain intensity at week 12 is shown in Figure 4 below. The figure is cumulative, such that patients whose change from baseline, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. A higher proportion of patients treated with TARGINIQ ER (55%) had at least a 30% reduction in pain score from screening to week 12 compared to placebo patients (41%). Also, a higher proportion of patients treated with TARGINIQ ER (37%) had at least a 50% reduction in pain score from screening to week 12 compared to placebo patients (25%).
Figure 4. Plot of Distribution of Responders Based on Pain Intensity at Week 12
16 HOW SUPPLIED/STORAGE AND HANDLING
TARGINIQ ER (oxycodone hydrochloride and naloxone hydrochloride extended-release
tablets) 10 mg/5 mg are capsule shaped, white film-coated tablets
debossed with “ONX” on one side and “10” on the other and are supplied
as child-resistant closure, opaque HDPE bottles of 100
(NDC 59011-520-01).
TARGINIQ ER (oxycodone hydrochloride and
naloxone hydrochloride extended-release tablets) 20 mg/10 mg are capsule
shaped, pink film-coated tablets debossed with “ONX” on one side and
“20” on the other and are supplied as child-resistant closure, opaque
HDPE bottles of 100
(NDC 59011-521-01).
TARGINIQ ER (oxycodone hydrochloride
and naloxone hydrochloride extended-release tablets) 40 mg/20 mg are
capsule shaped, yellow film-coated tablets debossed with “ONX” on
one side and “40” on the other and are supplied as child-resistant
closure, opaque HDPE bottles of 100
(NDC 59011-522-01).
Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant container, with a child-resistant closing.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients that the use of TARGINIQ ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share TARGINIQ ER with others and to take steps to protect TARGINIQ ER from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression including information that the risk is greatest when starting TARGINIQ ER or when the dose is increased and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store TARGINIQ ER securely and to dispose of unused TARGINIQ ER by flushing the tablets down the toilet.
Interaction with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if TARGINIQ ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.5), Drug Interactions (7)].
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].
Inform patients to avoid taking TARGINIQ ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TARGINIQ ER.
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].
Important Administration Instructions
Instruct patients how to properly take TARGINIQ ER, including the following:
- TARGINIQ ER is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved TARGINIQ ER tablets can result in a fatal overdose or other serious side effects (e.g., withdrawal symptoms) [see Dosage and Administration (2.1)].
- Do not discontinue TARGINIQ ER without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.7)].
Inform patients that TARGINIQ ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].
Inform patients that anaphylaxis has been reported with ingredients contained in TARGINIQ ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Neonatal Opioid Withdrawal
Syndrome
Inform female patients of reproductive
potential that prolonged use of TARGINIQ ER during pregnancy can result
in neonatal opioid withdrawal syndrome, which may be life-threatening
if not recognized and treated [see Warnings and Precautions
(5.3), Use in Specific Populations
(8.1)].
Embryo-Fetal Toxicity
Inform female patients of reproductive potential that TARGINIQ ER
can cause fetal harm and to inform the healthcare provider of a known
or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise patients that breastfeeding is not recommended during treatment with TARGINIQ ER [see Use in Specific Populations (8.2)]
Infertility
Inform patients that chronic use of opioids may cause
reduced fertility. It is not known whether these effects on fertility
are reversible [see Use in Specific Populations (8.3)].
Advise patients that TARGINIQ ER may be associated with symptoms possibly related to opioid withdrawal, including sweating, tremors, anxiety, chills, diarrhea, abdominal pain, irritability, and yawning, and to contact their prescriber if these symptoms occur.
Driving or Operating Heavy Machinery
Inform patients that TARGINIQ ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].
Disposal of Unused TARGINIQ ER
Advise patients to flush the unused tablets down the toilet when TARGINIQ ER is no longer needed.
Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product.
Purdue Pharma L.P. Stamford, CT 06901-3431
U.S. Patent Numbers: 6,228,863; 6,627,635; 8,822,487; 8,846,090; 8,846,091; 8,969,369; 9,056,051; 9,073,933; 9,084,729; 9,161,937; 9,168,252; 9,205,082; 9,283,216; 9,283,221; 9,345,701; 9,358,230; 9,474,750; 9,480,685; 9,511,066 and 9,522,919
| Medication GuideTARGINIQ™ ER (tar-gih-NEEK E-R)(oxycodone hydrochloride and naloxone hydrochloride extended-release tablets), CII | |
TARGINIQ ER
is:
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Important
information about TARGINIQ ER:
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Do not take
TARGINIQ ER if you have:
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| Before taking TARGINIQ ER, tell your healthcare provider if you have a history of: | |
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Tell your healthcare
provider if you are:
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When taking
TARGINIQ ER:
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While taking
TARGINIQ ER DO NOT:
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The possible
side effects of TARGINIQ ER are:
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This Medication Guide
has been approved by the U.S. Food and Drug Administration.
Issue: 12/2016
Targiniq ER 10 mg/5 mgNDC: 59011-520-01
Targiniq ER 20 mg/10 mgNDC: 59011-521-01
Targiniq ER 40 mg/20 mgNDC: 59011-522-01
| TARGINIQ ER oxycodone hydrochloride/naloxone hydrochloride tablet, film coated, extended release | ||||||||||||||||||||||||
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| TARGINIQ ER oxycodone hydrochloride/naloxone hydrochloride tablet, film coated, extended release | ||||||||||||||||||||||||
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| Labeler — Purdue Pharma LP (932323652) |
| Registrant — Purdue Pharma LP (932323652) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Purdue Pharmaceuticals L.P. | 132080875 | MANUFACTURE (59011-521), MANUFACTURE (59011-522), MANUFACTURE (59011-520) | |
Revised: 12/2016 Purdue Pharma LP
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