9/18. Fosnetupitant and Palonosetron - (AKYNZEO) -@-( Apr- 2018)- to prevent nausea and vomitting hihly emetogenic cancer therapy
Drug Name:9/18. Fosnetupitant and Palonosetron - (AKYNZEO) -@-( Apr- 2018)- to prevent nausea and vomitting hihly emetogenic cancer therapy
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
CYP3A4 Substrates: inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug for 6 days after single dosage administration of AKYNZEO; avoid concomitant CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of the CYP3A4 substrate
CYP3A4 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use
Indication:
BRIEF SUMMARY
FOSNETUPITANT AND PALONOSETRON- (April 2018)
Indn- To prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy
Comp- Capsules: 300 mg netupitant/0.5 mg palonosetron- For Injection: 235 mg fosnetupitant/0.25 mg palonosetron lyophilized powder in a single-dose vial for reconstitution - One capsule administered approximately 1 hour prior to the start of chemotherapy, with or without food.
ADR- Most common adverse reactions (=3%) for capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema
CI- None
WARNINGS-
Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the components of AKYNZEO, with or without known hypersensitivity to other 5-HT3 receptor antagonists.
Pat Inform-
1.Administration Advise patients to take capsules with or without food approximately 1 hour prior to the start of chemotherapy
2.Hypersensitivity Reactions- Advise patients that hypersensitivity reactions, including anaphylaxis, may occur in patients receiving Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while taking
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U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 9
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (=3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema
The safety profile of AKYNZEO for injection was generally similar to that seen with AKYNZEO capsules.
Contra-Indications:
CONTRAINDICATIONS None
WARNINGS AND PRECAUTIONS
Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the components of AKYNZEO, with or without known hypersensitivity to other 5-HT3 receptor antagonists.
Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue AKYNZEO and initiate supportive treatment. If concomitant use of AKYNZEO with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome.
DRUG INTERACTIONS
CYP3A4 Substrates: inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug for 6 days after single dosage administration of AKYNZEO; avoid concomitant CYP3A4 substrates for one week, if feasible. If not avoidable, consider dose reduction of the CYP3A4 substrate
CYP3A4 Inducers (e.g., rifampin): decreased plasma concentrations of netupitant; avoid use
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause fetal harm
Hepatic Impairment: Avoid use in patients with severe hepatic impairment
Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease
Dosages/ Overdosage Etc:
DOSAGE FORMS AND STRENGTHS
Capsules: 300 mg netupitant/0.5 mg palonosetron For Injection: 235 mg fosnetupitant/0.25 mg palonosetron lyophilized powder in a single-dose vial for reconstitution
Patient Information:
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Patient Information).
1.Administration Advise patients to take AKYNZEO capsules with or without food approximately 1 hour prior to the start of chemotherapy
2.Hypersensitivity Reactions- Advise patients that hypersensitivity reactions, including anaphylaxis, may occur in patients receiving AKYNZEO. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while taking AKYNZEO
3.Serotonin Syndrome- Advise patients of the possibility of serotonin syndrome, especially with concomitant use of AKYNZEO and another serotonergic agent such as medications to treat depression and migraines.
4.Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms
5.Pregnancy Inform female patients of reproductive potential that AKYNZEO may cause fetal harm and to inform their prescriber of a known or suspected pregnancy..
Manufactured by
Helsinn Birex Pharmaceuticals, Dublin, Ireland for Helsinn Healthcare SA, Switzerland Distributed by Helsinn Therapeutics (U.S.), Inc., Iselin, NJ 08830, under license of Helsinn Healthcare SA, Switzerland
AKYNZEO is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK-1) receptors. Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.
Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5 HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.
2. Pharmacodynamics
NK-1 Receptor Occupancy -The receptor occupancy of netupitant was measured in a human Positron Emission Tomography (PET) study. Netupitant was shown to cross the blood brain barrier with a NK-1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after oral administration of 300 mg netupitant.
Cardiac Electrophysiology -An AKYNZEO oral dose of 600 mg netupitant (2 times the recommended dose) and 1.5 mg palonosetron (3 times the recommended dose) did not prolong the QT interval to any clinically relevant extent.
The recommended dose of AKYNZEO for injection (235 mg fosnetupitant and 0.25 mg palonosetron) did not prolong the QT interval to any clinically relevant extent.
3. Pharmacokinetics- Netupitant and Palonosetron- Absorption - Upon single oral administration of AKYNZEO capsules to healthy subjects and patients, netupitant and palonosetron were measurable within 1 hour after administration and reached the maximum concentration (Cmax) in approximately 4 to 5 hours
Following oral administration, the absolute bioavailability of palonosetron was approximately 97%. When AKYNZEO capsules were administered under fed conditions, the systemic exposure to netupitant and palonosetron was similar to the exposure under fasting conditions.
Distribution- After single oral administration of AKYNZEO capsules, netupitant and palonosetron were widely distributed throughout the body.
Elimination- Netupitant- After a single dose of AKYNZEO capsules, netupitant is eliminated from the body in a multiexponential fashion and the mean ± SD of apparent elimination half-life was of 96 ? 59 hours in healthy subjects and 80 ± 29 hours in cancer patients.
Metabolism- Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK-1) receptor.
The mean AUCinf for metabolites M1, M2 and M3 was 29%, 14% and 33% of netupitant, respectively. The median tmax for metabolite M2 was 5 hours and was about 17 to 32 hours for metabolites M1 and M3, respectively.
Excretion- After a single oral administration of [14C]netupitant, approximately half the administered radioactivity was recovered from urine and feces within 120 hours of dosing. The total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and feces collected over 336 hours, respectively, and the mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1% suggesting renal clearance is not a significant elimination route for the netupitant-related entities.
About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose.
Elimination- Palonosetron -Following oral administration of AKYNZEO capsules in healthy subjects and cancer patients, the mean ( ? SD) of half-life of palonosetron was 44 ? 15 hours and 50 ± 16 hours, respectively, whereas the mean ? SD of total body clearance (CL/F) was 9.6 ? 2.7 L/h and 10.0 ? 3.4 L/h, respectively.
Metabolism- Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-Shydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.
Specific Populations
Geriatric Patients In cancer patients receiving AKYNZEO capsules, population pharmacokinetic analysis indicated that age (within the range of 29 to 75 years) did not influence the pharmacokinetics of netupitant or palonosetron.
In healthy elderly subjects (greater than 65 years of age) the mean AUCinf and Cmax was 25% and 36% higher, respectively, for netupitant, and 37% and 10% higher, respectively, for palonosetron compared to those in healthy younger adults (22 to 45 years of age).
Patients with Renal Impairment- Population pharmacokinetic analysis showed that mild and moderate renal impairment (creatinine clearance 30 to 60 mL/min) did not significantly affect the pharmacokinetics of netupitant in cancer patients. Netupitant has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. In a study with intravenous palonosetron, total systemic exposure to palonosetron increased by approximately 28% in patients with severe renal impairment relative to healthy subjects.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
Pregnancy: May cause fetal harm
Hepatic Impairment: Avoid use in patients with severe hepatic impairment
Renal Impairment: Avoid use in patients with severe renal impairment or end-stage renal disease
USE IN SPECIFIC POPULATIONS
1.Pregnancy Risk Summary- Limited available data with AKYNZEO use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes.
Based on animal data from netupitant studies, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated populations are 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.
2. Lactation Risk Summary- There are no data on the presence of netupitant (or fosnetupitant) or palonosetron in human milk, the effects on the breastfed infant, or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AKYNZEO and any potential adverse effect on the breastfed child from AKYNZEO or from the underlying maternal condition.
3.Pediatric Use- The safety and effectiveness of AKYNZEO in patients below the age of 18 years have not been established.
4.Geriatric Use- Of the 1169 adult cancer patients treated with AKYNZEO capsules in clinical studies, 18% were aged 65 and over, while 2% were aged 75 years and over.
The nature and frequency of adverse reactions were similar in elderly and younger patients. Exploratory analyses of the impact of age on efficacy were performed in the two trials that compared AKYNZEO to palonosetron
5. Hepatic Impairment- No dosage adjustment for AKYNZEO is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 8).
Limited data are available with AKYNZEO in patients with severe hepatic impairment (Child-Pugh score greater than 9).
Avoid use of AKYNZEO in patients with severe hepatic impairment
6.Renal Impairment- No dosage adjustment for AKYNZEO is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 to 60 mL/min).
The pharmacokinetics and safety of netupitant have not been studied in patients with severe renal impairment. Severe renal impairment (creatinine clearance < 30 mL/min) did not substantially affect pharmacokinetics of palonosetron.
The pharmacokinetics for netupitant and palonosetron were not studied in patients with end-stage renal disease requiring hemodialysis.
Avoid use of AKYNZEO in patients with severe renal impairment or end-stage renal disease.
OVERDOSAGE
In the event of overdose, AKYNZEO should be discontinued and general supportive treatment and monitoring should be provided.
Because of the antiemetic activity of AKYNZEO, druginduced emesis may not be effective. Dialysis studies have not been performed; due to the large volume of distribution, dialysis is unlikely to be an effective treatment for AKYNZEO overdose. A total of 33 adult cancer patients were administered oral palonosetron at a dose of 90 mcg/kg (approximately 12 times the recommended dose in AKYNZEO capsules), as part of a dose ranging study and had a similar incidence of adverse reactions compared to lower doses. A single dose of 600 mg (2 times the recommended dose in AKYNZEO capsules) of oral netupitant was administered to 49 healthy subjects and a similar incidence of adverse reactions was observed when compared to lower doses of netupitant in cancer patients and healthy subjects. 11 DESCRIPTION AKYNZEO (300 mg netupitant/0.5 mg palonosetron) capsules are an oral combination product of netupitant, a substance P/neurokinin 1 (NK-1) receptor antagonist, and palonosetron hydrochloride, a serotonin-3 (5-HT3) receptor antagonist. Both netupitant and palonosetron hydrochloride are anti-nausea and anti-emetic agents. Netupitant is chemically described: 2-[3,5-bis(trifluoromethyl)phenyl]-N, 2 dimethyl-N-[4-(2 methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl] propanamide. The empirical formula is C30H32F6N4O, with a molecu