Letermovir- Anti-infective- Prevymis -@-(2017)
Drug Name:Letermovir- Anti-infective- Prevymis -@-(2017)
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
Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full prescribing information prior to and during treatment for potential drug interactions.
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 37
Name of the Drug- Prevymis
Active Ingredient- Letermovir
Pharmacological Classification-
To prevent infection of bone marrow transplant
Date of Approval- 11-8-2017
(Ref- FDA approved List 2017)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PREVYMIS safely and effectively. See full prescribing information for PREVYMIS.
PREVYMIS™ (letermovir) tablets, for oral use PREVYMIS™ (letermovir) injection, for intravenous use
Initial U.S. Approval: 2017
INDICATIONS AND USAGE
PREVYMIS is a CMV DNA terminase complex inhibitor indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.
Contra-Indications:
CONTRAINDICATIONS
PREVYMIS is contraindicated with:
Pimozide.
Ergot A kaloids.
Pitavastatin and simvastatin when co-administered with cyclosporine.
WARNINGS AND PRECAUTIONS
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions:
The concomitant use of PREVYMIS with certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consult the full prescribing information for contraindications and dosage recommendations for concomitant drugs.
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Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
PREVYMIS is a CMV DNA terminase complex inhibitor indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
DOSAGE AND ADMINISTRATION
480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-transplant.
Dosage Adjustment: If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
DOSAGE FORMS AND STRENGTHS
Tablet: 240 mg; 480 mg.
Injection: 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) in a single-dose vial.
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Drug Interactions
Inform patients that PREVYMIS may interact with some drugs; therefore, advise patients to report the use of any prescription, non-prescription medication, or herbal products to their healthcare provider
Administration
Inform patients that it is important not to miss or skip doses and to take PREVYMIS for the duration that is recommended by the healthcare provider. Instruct patients that if they miss a dose of PREVYMIS, they should take it as soon as they remember.
If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.
Storage
Advise patients to store PREVYMIS tablets in the original package until use
HOW SUPPLIED/STORAGE AND HANDLING
Tablets:
Each PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with “591” on one side and Merck logo on the other side. Each PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with “595” on one side and Merck logo on the other side.
For patent information: www.merck.com/product/patent/home.html
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1.Mechanism of Action
PREVYMIS is an antiviral drug against CMV
2. Pharmacodynamics
Cardiac Electrophysiology
In a thorough QT trial in healthy subjects, letermovir at the therapeutic IV dose or at a dose of 2 times the approved IV dose did not prolong QTc to any clinically relevant extent.
3. Pharmacokinetics
Pharmacokinetics in Healthy Subjects
Treatment Regimen
480 mg oral once daily
Steady-state geometric mean AUC and Cmax of PREVYMIS
Cmax: 13,000 ng/mL
AUC: 71,500 ng•hr/mL
Time to steady-state 9-10 days
Absorption
Bioavailability Healthy subjects administered PREVYMIS without cyclosporine: 94% at an oral dose range of 240 mg to 480 mg
Median Tmax (hr) 45 min to 2.25 hr
Effect of food (relative to fasting) ‡ AUC: 99.63% [84.27% - 117.80%]
Cmax: 129.82% [104.35% -161.50%]
Distribution
Mean steady-state volume of distribution
45.5 L following IV administration in HSCT recipients
% In vitro bound to human plasma proteins 99% across the concentration range of 0.2 to 50 mg/L
In vitro blood-to plasma ratio 0.56 across the concentration range of 0.1 to 10 mg/L
Metabolism
In vitro metabolism UGT1A1/1A3 (minor)
Drug-related component in plasma 97% unchanged parent
No major metabolites detected in plasma
Elimination
Route of elimination Hepatic uptake (OATP1B1/3)
Mean terminal t1/2 (hr) 12 hrs after dosing of PREVYMIS 480 mg IV once daily
% of dose excreted in feces§ 93%
% of dose excreted in urine§ <2%
% of unchanged drug excreted in feces§ 70%
Populations Pediatric Population
The pharmacokinetics of letermovir in patients less than 18 years of age have not been evaluated.
Age, Gender, Race, and Weight Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did not have a clinically significant effect on the pharmacokinetics of letermovir.
Renal Impairment
Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects.
Hepatic Impairment
Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects.
Drug Interaction
Studies Drug interaction studies were performed in healthy subjects with PREVYMIS and drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes.
In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD).
The risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
2. Lactation
Risk Summary It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PREVYMIS and any potential adverse effects on the breastfed child from PREVYMIS or from the underlying maternal condition.
3. Females and Males of Reproductive Potential
Infertility There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats
4. Pediatric Use
Safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.
5.Geriatric Use
Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of PREVYMIS is required based on age .
6. Renal Impairment
For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment
The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
In patients with CLcr less than 50 mL/min receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.
7. Hepatic Impairment
No dosage adjustment of PREVYMIS is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (ChildPugh Class C) hepatic impairment
OVERDOSAGE
There is no specific antidote for overdose with PREVYMIS. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment be instituted.
It is unknown whether dialysis will result in meaningful removal of PREVYMIS from systemic circulation.
