Symproic

Naldemedine tosylate has the following uses:

Naldemedine tosylate is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.1

General

Naldemedine tosylate is available in the following dosage form(s) and strength(s):

Tablets: 0.2 mg of naldemedine.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Administration

• Alteration of analgesic dosing regimen prior to initiating naldemedine tosylate is not required.1

• Patients receiving opioids for less than 4 weeks may be less responsive to naldemedine tosylate.1

• Discontinue naldemedine tosylate if treatment with the opioid pain medication is also discontinued.1

Dosage

• In adults, the recommended dosage is 0.2 mg once daily with or without food.1

Symproic is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases). Take into account the overall risk-benefit profile when using Symproic in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue Symproic in patients who develop this symptom [see Contraindications (4)].

Opioid Withdrawal

Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with Symproic [see Adverse Reactions (6.1)].

Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using Symproic in such patients. Monitor for symptoms of opioid withdrawal in such patients.

Pregnancy

Risk Summary

There are no available data with naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when Symproic is used in pregnant women [see Clinical Considerations]. Symproic should be used during pregnancy only if the potential benefit justifies the potential risk.

In a rat embryo-fetal development study following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day [see Data]. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.

Data

Animal Data

In rats, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures (AUC) at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures (AUC) at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures (AUC) at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed.

In the pre- and postnatal development study, pregnant rats were administered naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures (AUC) at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures (AUC) at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.

Lactation

Risk Summary

There is no information regarding the presence of naldemedine in human milk, the effects on the breastfed infant, or the effects on milk production. Naldemedine was present in the milk of rats [see Data]. Because of the potential for serious adverse reactions, including opioid withdrawal in breastfed infants, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. If drug is discontinued in order to minimize drug exposure to a breastfed infant, advise women that breastfeeding may be resumed 3 days after the final dose of Symproic.

Data

Drug-related radioactivity was transferred into milk of lactating rats following a single oral dose of 1 mg/kg [carbonyl-14C]-naldemedine.

Pediatric Use

The safety and effectiveness of Symproic have not been established in pediatric patients.

Geriatric Use

Of 1163 patients in clinical studies exposed to Symproic, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of naldemedine were observed [see Clinical Pharmacology (12.3)].

Hepatic Impairment

The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine has not been evaluated. Avoid use of Symproic in patients with severe hepatic impairment. No dose adjustment of Symproic is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

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

Administration

Advise patients to discontinue Symproic if treatment with the opioid pain medication is also discontinued.

Gastrointestinal Perforation

Advise patients to discontinue Symproic and to promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain [see Warnings and Precautions (5.1)].

Opioid Withdrawal

Advise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking Symproic and to contact their healthcare provider if these symptoms occur [see Warnings and Precautions (5.2)].

Pregnancy

Advise females of reproductive potential, who become pregnant or are planning to become pregnant, that the use of Symproic during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood-brain barrier [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with Symproic and for 3 days after the final dose [see Use in Specific Populations (8.2)].

Symproic is a registered trademark of Shionogi & Co., Ltd.

Manufactured for: Shionogi Inc., Florham Park, NJ 07932
Manufactured by: QS Pharma LLC, Boothwyn, PA 19061
Distributed by: Purdue Pharma L.P., Stamford, CT 06901

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                                                                                                                                                                                                                         Revised: 8/2017

Symproic 90 Tablets
NDC: 59011-523-90

Symproic 7 Tablets
NDC: 59011-523-07

See Important information.

The most common side effects include stomach (abdomen) pain, diarrhea, and nausea.

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. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Medicines are sometimes prescribed for purposes other than those in a Medication Guide. Do not take this medicine for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information that is written for health professionals.

Active Ingredient: naldemedine tosylate

Inactive ingredients: D-mannitol, croscarmellose sodium, magnesium stearate, hypromellose, talc, and yellow ferric oxide.

Applies to naldemedine: oral tablet

General

The most commonly reported adverse reactions have included abdominal pain, diarrhea, and nausea.[Ref]

Hypersensitivity

Frequency not reported: Bronchospasm, rash

During clinical trials, 2 patients developed symptoms of hypersensitivity. One had bronchospasm and the other had a rash.

Psychiatric

Adverse reactions consistent with opioid withdrawal have been reported. These reactions may have included hyperhidrosis, hot flush or flushing, chills, tremor, tachycardia, anxiety, agitation, yawning, rhinorrhea, increased lacrimation, sneezing, feeling cold, pyrexia, vomiting, diarrhea, or abdominal pain. The incidence of adverse reactions of opioid withdrawal in 2 pooled studies was similar to placebo (8/542 vs 3/546); in a 52-week study the incidence in drug-treated patients was 3% (20/621) versus 1% (9/619) for placebo.

Common (1% to 10%): Opioid withdrawal

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 11%)
Common (1% to 10%): Diarrhea, nausea, gastroenteritis, vomiting

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

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.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Symproic (naldemedine), please talk with the doctor, pharmacist, or other health care provider.
• 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.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Symproic. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Symproic.

Review Date: November 1, 2017

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.