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

figure-4
(click image for full-size original)

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.

CAUTION

DEA FORM REQUIRED

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

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.

Accidental Ingestion

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)].

Serotonin Syndrome

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)].

MAOI Interaction

Inform patients to avoid taking TARGINIQ ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TARGINIQ ER.

Adrenal Insufficiency

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)].

Hypotension

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)].

Anaphylaxis

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)].

Pregnancy

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)].

Lactation

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)].

Opioid Withdrawal Symptoms

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.

Constipation

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

©2016, Purdue Pharma L.P.

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:
  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily, around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
  • Not for use to treat pain that is not around-the-clock.
Important information about TARGINIQ ER:
  • Get emergency help right away if you take too much TARGINIQ ER (overdose). When you first start taking TARGINIQ ER, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking TARGINIQ ER with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
  • Never give anyone else your TARGINIQ ER. They could die from taking it. Store TARGINIQ ER away from children and in a safe place to prevent stealing or abuse. Selling or giving away TARGINIQ ER is against the law.
Do not take TARGINIQ ER if you have:
  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.
Before taking TARGINIQ ER, tell your healthcare provider if you have a history of:
  • head injury, seizures
  • liver, kidney, thyroid or heart problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems
  • problems urinating
  • pancreas or gallbladder problems
Tell your healthcare provider if you are:
  • pregnant or planning to become pregnant. Prolonged use of TARGINIQ ER during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Not recommended during treatment with TARGINIQ ER. It may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking TARGINIQ ER with certain other medicines can cause serious side effects that could lead to death.
When taking TARGINIQ ER:
  • Do not change your dose. Take TARGINIQ ER exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose every 12 hours at the same time every day. Do not take more than your prescribed dose in 12 hours. If you miss a dose, take your next dose at your usual time.
  • Swallow TARGINIQ ER whole. Do not cut, break, chew, crush, dissolve, snort, or inject TARGINIQ ER because this may cause you to overdose and die.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • Do not stop taking TARGINIQ ER without talking to your healthcare provider.
  • After you stop taking TARGINIQ ER, flush any unused tablets down the toilet.
While taking TARGINIQ ER DO NOT:
  • Drive or operate heavy machinery, until you know how TARGINIQ ER affects you. TARGINIQ ER can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with TARGINIQ ER may cause you to overdose and die.
The possible side effects of TARGINIQ ER are:
  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, anxiety, and sweating. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
Call your healthcare provider if you get symptoms that may be related to opioid withdrawal including tremors, chills, diarrhea, irritability, and yawning.These are not all the possible side effects of TARGINIQ ER. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. Manufactured by: Purdue Pharma L.P., Stamford, CT 06901-3431, www.purduepharma.com or call 1-888-726-7535

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 10 mg/5 mg
(click image for full-size original)

Targiniq ER 20 mg/10 mgNDC: 59011-521-01

Targiniq ER 20 mg/10 mg
(click image for full-size original)

Targiniq ER 40 mg/20 mgNDC: 59011-522-01

Targiniq ER 40 mg/20 mg
(click image for full-size original)
TARGINIQ ER oxycodone hydrochloride/naloxone hydrochloride tablet, film coated, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-521
Route of Administration ORAL DEA Schedule CII
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OXYCODONE HYDROCHLORIDE (OXYCODONE) OXYCODONE HYDROCHLORIDE 20 mg
NALOXONE HYDROCHLORIDE (NALOXONE) NALOXONE HYDROCHLORIDE 10 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE
STEARYL ALCOHOL
ETHYLCELLULOSES
POVIDONES
TALC
MAGNESIUM STEARATE
POLYVINYL ALCOHOL
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE RED
Product Characteristics
Color PINK Score no score
Shape CAPSULE Size 10mm
Flavor Imprint Code ONX;20
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:59011-521-01 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205777 01/01/2020
TARGINIQ ER oxycodone hydrochloride/naloxone hydrochloride tablet, film coated, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-520
Route of Administration ORAL DEA Schedule CII
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OXYCODONE HYDROCHLORIDE (OXYCODONE) OXYCODONE HYDROCHLORIDE 10 mg
NALOXONE HYDROCHLORIDE (NALOXONE) NALOXONE HYDROCHLORIDE 5 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE
STEARYL ALCOHOL
ETHYLCELLULOSES
POVIDONES
TALC
MAGNESIUM STEARATE
POLYVINYL ALCOHOL
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 5mm
Flavor Imprint Code ONX;10
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:59011-520-01 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205777 01/01/2020
TARGINIQ ER oxycodone hydrochloride/naloxone hydrochloride tablet, film coated, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-522
Route of Administration ORAL DEA Schedule CII
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OXYCODONE HYDROCHLORIDE (OXYCODONE) OXYCODONE HYDROCHLORIDE 40 mg
NALOXONE HYDROCHLORIDE (NALOXONE) NALOXONE HYDROCHLORIDE 20 mg
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE
STEARYL ALCOHOL
ETHYLCELLULOSES
POVIDONES
TALC
MAGNESIUM STEARATE
POLYVINYL ALCOHOL
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE YELLOW
Product Characteristics
Color YELLOW Score no score
Shape CAPSULE Size 14mm
Flavor Imprint Code ONX;40
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:59011-522-01 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205777 01/01/2020
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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