DRUG INTERACTIONS

 

Strong CYP3A inducers (e.g., rifampin): 

Decreased naldemedine concentrations; avoid concomitant use 

 

Other opioid antagonists:

 Potential for additive effect and increased risk of opioid withdrawal;

 avoid concomitant use 

 

Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors:

 Increased naldemedine concentrations; monitor for adverse reactions 

 

P-gp inhibitors (e.g., cyclosporine): 

Monitor for adverse reactions 

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  9

  

Name of the  Drug-        Symporic

 

Active Ingredient-           Naldemedine                                                                                                                                                                                                           Pharmacological Classification- 

 

                       For the treatment of opioid-induced constipation                 

                                                                                                                           

Date of Approval-          03-23-2017

 

 (Ref- FDA approved List 2017)                                                                                                                                                                                                                                                                                                                                                      HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use 

SYMPROIC safely and effectively. 

See full prescribing information for SYMPROIC.

 

SYMPROIC® (naldemedine) tablets, for oral use, C-II 

Initial U.S. Approval: 2017

 

INDICATIONS AND USAGE

 

SYMPROIC is an opioid antagonist indicated for the treatment of 

opioid-induced constipation (OIC) in adult patients with 

chronic non-cancer pain                                                

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS

 

Most common adverse reactions (.2%) are: 

abdominal pain, diarrhea, and nausea. 

CONTRAINDICATIONS

 

Patients with known or suspected gastrointestinal obstruction or

 at increased risk of recurrent obstruction 

 

Patients with a history of a hypersensitivity reaction to naldemedine

 

 

WARNINGS AND PRECAUTIONS

 

Gastrointestinal perforation: 

Consider the overall risk benefit in patients with known or suspected 

lesions of the GI tract. Monitor for severe, persistent, or worsening 

abdominal pain; discontinue if development of symptoms 

 

Opioid withdrawal: 

Consider the overall risk benefit in patients with disruptions to the 

blood-brain barrier. Monitor symptoms of opioid withdrawal 

 

INDICATIONS AND USAGE

 

SYMPROIC is an opioid antagonist indicated for the treatment of 

opioid-induced constipation (OIC) in adult patients with 

chronic non-cancer pain 

 

DOSAGE AND ADMINISTRATION

 

Administration 

Alteration of analgesic dosing regimen prior to initiating 

SYMPROIC is not required

 

Patients receiving opioids for less than 4 weeks may be less

 responsive to SYMPROIC

 

Discontinue SYMPROIC if treatment with the opioid pain 

medication is also discontinued

 

Dosage :

In adults, the recommended dosage is 0.2 mg once daily 

with or without food

 

DOSAGE FORMS AND STRENGTHS

Tablets: 0.2 mg naldemedine 

 

 PATIENT COUNSELING INFORMATION

 

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.

 

 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.

 

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..

 

Lactation-

 Advise women that breastfeeding is not recommended during treatment 

with SYMPROIC and for 3 days after the final dose.

 

SYMPROIC is a trademark of the Shionogi group.

Manufactured for: Shionogi Inc., 300 Campus Drive, Florham Park, NJ 07932

Reference ID: 4074014

 

CLINICAL PHARMACOLOGY

 

1.Mechanism of Action

Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and

 kappa-opioid receptors. Naldemedine functions as a peripherally-acting

 mu-opioid receptor antagonist in tissues such as the gastrointestinal tract,

 thereby decreasing the constipating effects of opioids.

 

Naldemedine is a derivative of naltrexone to which a side chain has been added

 that increases the molecular weight and the polar surface area, thereby reducing

 its ability to cross the blood-brain barrier (BBB). 

 

Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. 

Based on these properties, the CNS penetration of naldemedine is expected

 to be negligible at the recommended dose levels, limiting the potential for 

interference with centrally-mediated opioid analgesia.

 

2. Pharmacodynamics

Use of opioids induces slowing of gastrointestinal motility and transit. 

Antagonism of gastrointestinal mu-opioid receptors by naldemedine inhibits

 opioid-induced delay of gastrointestinal transit time.

 

 Effect on Cardiac Repolarization

 At a dose up to 5-times the recommended dose, SYMPROIC does not prolong

 the QT interval to any clinically relevant extent.

 

3. Pharmacokinetics

 Absorption

 Following oral administration, naldemedine is absorbed with the time to achieve

 peak concentrations (Tmax) of approximately 0.75 hours in a fasted state. 

 

 Across the range of doses evaluated, the maximum plasma concentration (Cmax) 

 and area under the plasma concentration-time curve (AUC) increased in a 

 dose-proportional or almost dose-proportional manner. 

Accumulation was minimal following multiple daily doses of naldemedine.

 

Food Effect

 A high-fat meal decreased the rate, but not the extent of naldemedine absorption.

 The Cmax was decreased by approximately 35% and time to achieve Cmax was

 delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state,

 whereas there was no meaningful change in the AUC in the fed state.

 

Distribution

Plasma protein binding of naldemedine in humans is 93% to 94%. 

The mean apparent volume of distribution during the terminal phase (Vz/F) is 155 L.

 

Elimination

The terminal elimination half-life of naldemedine is 11 hours.

 

Excretion

 Following oral administration of [14C]-labeled naldemedine, the total amount

 of radioactivity excreted in the urine and feces was 57% and 35% of the 

 administered dose of naldemedine, respectively. The amount of naldemedine 

 excreted unchanged in the urine was approximately 16% to 18% of the 

 administered dose. 

 

 Benzamidine was the most predominant metabolite excreted in the urine and

 feces, representing approximately

 

Metabolism

Naldemedine is primarily metabolized by CYP3A to nor-naldemedine, 

with minor contribution from UGT1A3 to form naldemedine 3-G. 

Nor-naldemedine and naldemedine 3-G have been shown to have 

antagonistic activity for opioid receptors, with less potent effect than 

naldemedine.

 

USE IN SPECIFIC POPULATIONS

 

1.Pregnancy: 

May precipitate opioid withdrawal in a fetus 

 

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 

 

 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 .

 

 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).

 

 

2. Lactation

Discontinue drug or breastfeeding taking into consideration importance 

of drug to mother 

 

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.

 

3. Pediatric Use

The safety and effectiveness of SYMPROIC have not been established in pediatric 

 patients.

 

4. 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.

 

5.Hepatic Impairment

Avoid in severe 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 

 

 DRUG ABUSE AND DEPENDENCE

 Controlled Substance

 SYMPROIC contains naldemedine, a Schedule II controlled substance.

 

OVERDOSAGE

 Single doses of naldemedine up to 100 mg (500 times the recommended dose)

  and multiple doses of up to 30 mg (150 times the recommended dose) 

  for 10 days have been administered to healthy subjects in clinical studies. 

 

  Dose-dependent increases in gastrointestinal-related adverse reactions, 

  including abdominal pain, diarrhea, and nausea, were observed.

 

  Single doses of naldemedine up to 3 mg (15 times the recommended dose) 

  and multiple doses of 0.4 mg (twice the recommended dose) for 28 days have 

   been administered to patients with OIC in clinical studies. 

  

   Dose-dependent increases in gastrointestinal-related adverse reactions, 

   including abdominal pain, diarrhea, nausea, and vomiting, were observed. 

  Also, chills, hyperhidrosis, and dizziness were reported more frequently 

  at 1 and 3 mg doses and hyperhidrosis at the 0.4 mg dose.

 

  No antidote for naldemedine is known. Hemodialysis is not an effective means 

  to remove naldemedine from the blood .