DRUG INTERACTIONS-

• Reduce to or continue at 115 mg/m2 twice daily with concomitant use of weak CYP3A inhibitors

 • See Full Prescribing Information for additional information regarding drug interactions

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  42

ADVERSE REACTIONS -

 The most common adverse reactions (incidence =25%) are vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase

WARNINGS AND PRECAUTIONS-

• Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions: Prior to and during treatment, consider potential for drug interactions and review concomitant medications; monitor for adverse reactions

 • Laboratory Abnormalities: Monitor for changes in electrolytes, complete blood counts, and liver enzymes

 • Nephrotoxicity: Caused nephrotoxicity in rats. Monitor renal function at regular intervals

 • Retinal Toxicity: Caused rod-dependent, low-light vision decline in monkeys. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes

 • Impaired Fertility: Caused impaired fertility in female rats, impaired fertility and testicular toxicity in male rats, and toxicity in the male reproductive tract in monkeys. Advise females and males of reproductive potential of the animal fertility findings

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions- Inform patients that hypersensitivity reactions have been seen in patients receiving VEKLURY during and after infusion. Advise patients to inform their healthcare provider if they experience any of the following: changes in heart rate; fever; shortness of breath, wheezing; swelling of the lips, face, or throat; rash; nausea; sweating; or shivering [see Warnings and Precautions (5.1)].

Increased Risk of Transaminase Elevations- Inform patients that VEKLURY may increase the risk of hepatic laboratory abnormalities.

Advise patients to alert their healthcare provider immediately if they experience any symptoms of liver inflammation.

Drug Interactions- Inform patients that VEKLURY may interact with other drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including chloroquine phosphate or hydroxychloroquine sulfate.

Pregnancy Registry- Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in individuals exposed to VEKLURY during pregnancy.

Pregnancy- Inform patients to notify their healthcare provider immediately in the event of a pregnancy.

Lactation- Inform mothers that it is not known whether VEKLURY can pass into their breast milk.

VEKLURY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2022 Gilead Sciences, Inc. All rights reserved

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

2. Pharmacodynamics -No formal pharmacodynamic studies have been conducted with ZOKINVY.

3 Pharmacokinetics-                                                                                                            The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized in Table 6. T

Summary of Pharmacokinetic Parameters of Lonafarnib at Steady State after Oral Administration Twice Daily to Patients with HGPS Lonafarnib Dose Median (range) tmax (hr) Mean (SD) Cmax (ng/mL) Mean (SD) AUC0-8hr (ng*hr/mL) Mean (SD) AUCtau (ng*hr/mL) 115 mg/m2 N 23 23 23 15 Results 2 (0, 6) 1777 (1083) 9869 (6327) 12365 (9135) 150 mg/m2 N 18 18 18 8 Results 4 (0, 12) 2695 (1090) 16020 (4978) 19539 (6434)

Absorption -                                                                                                                  The absolute bioavailability of lonafarnib following oral administration has not been determined.

Following oral administration of lonafarnib 75 mg and 100 mg twice daily in healthy subjects under fasted conditions, the geometric mean (CV%) maximum peak plasma concentrations of lonafarnib were 834 (32%) ng/mL and 964 (32%) ng/mL, respectively. 

Effect of Food-

 Following a single oral dose of 75 mg lonafarnib in healthy subjects, the Cmax decreased 55% and AUC decreased 29% with a high-fat meal (approximately 43% fat of the total 952 calories) compared to fasted conditions. Cmax decreased 25% and AUC decreased 21% with a low-fat meal (approximately 12% fat of the total 421 calories) compared to fasted conditions.

Distribution-

 In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 µg/mL. The apparent volumes of distribution were 87.8 L and 97.4 L, respectively, at steady state following oral administration of lonafarnib 100 mg and 75 mg twice daily in healthy subjects.

Elimination -

The mean half-life was approximately 4 to 6 hours following oral administration of lonafarnib 100 mg twice daily in healthy subjects.

Metabolism-                                                                                                             Lonafarnib is primarily metabolized by CYP3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 in vitro.

Excretion --

Following an oral administration of 104 mg [14C]-lonafarnib under fasted conditions in healthy subjects, approximately 62% of the total radiolabeled dose was recovered in feces and <1% of the total radiolabeled dose was recovered in urine up to 240 hours post-dose.

The two most predominant metabolites were HM17 and HM21 (an active metabolite) accounting for 15% and 14% of plasma radioactivity, respectively.

Specific Populations -

Patients with Renal Impairment or Hepatic Impairment-                                            ZOKINVY has not been studied in patients with renal impairment or in patients with hepatic impairment. Male and

Female Patients-                                                                                                            Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib AUC and Cmax were 44% and 26% higher in female subjects, respectively, compared to male subjects. The observed exposure difference by sex in healthy subjects is not considered clinically meaningful.

Geriatric Patients -

Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib AUC and Cmax were 59% and 27% higher in subjects =65 years, respectively, compared to subjects 18 to 45 years of age.

The observed higher exposure in geriatric subjects is not considered clinically relevant. 

Drug Interaction Studies-

In Vitro Studies Lonafarnib is a CYP3A substrate and a potent CYP3A time-dependent and mechanism-based inhibitor. Lonafarnib is an inhibitor of CYP2C8 and CYP2C19. Lonafarnib is not considered an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6.

Lonafarnib is unlikely to be an inducer of CYP1A2, CYP2B6, and CYP3A. Lonafarnib is not a substrate of transporters OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp. Lonafarnib is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP.

Clinical Studies:                                                                                                                   Effects of other Drugs on Lonafarnib CYP3A inhibitors Lonafarnib is a sensitive substrate for CYP3A. With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A inhibitor) once daily for 5 days, the Cmax and AUC of lonafarnib were increased by 270% and 425%, respectively, as compared to lonafarnib administered alone in healthy subjects 

Drug Interactions-

. CYP2C9 inhibitors Coadministration with CYP2C9 inhibitors may increase lonafarnib AUC and Cmax. A drug-drug interaction study of ZOKINVY with CYP2C9 inhibitors has not been conducted 

CYP3A inducers With coadministration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin once daily for 8 days, the Cmax of lonafarnib was reduced by 92% and the AUC was reduced by 98%, as compared to without rifampin coadministration in healthy subjects

Clinical Studies:

Effects of Lonafarnib on other Drugs CYP3A Substrates Lonafarnib is a strong inhibitor of CYP3A.

With coadministration of a single oral dose of 3 mg midazolam with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the Cmax and AUC of midazolam were increased by 180% and 639%, respectively 

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary-

Based on findings from animal studies, ZOKINVY can cause embryofetal harm when administered to a pregnant woman.

There are no human data on ZOKINVY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Advise pregnant women of the risk to a fetus. In animal reproduction studies, oral administration of lonafarnib to pregnant rats during organogenesis produced embryo-fetal toxicity at exposures that were 1.2-times the human exposure at the recommended dose of 150 mg/m2 twice daily.

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.

No effects in offspring were observed in a pre- and postnatal development study in rats with maternal administration of up to 20 mg/kg/day orally (AUC lower t

8.2 Lactation Risk Summary-

 There are no data on the presence of ZOKINVY in human milk, the effects on the breastfed infant, or the effects on milk production. Lonafarnib is excreted in rat milk 

When a drug is present in animal milk, it is likely that the drug will be present in human milk. 

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOKINVY and any potential adverse effects of the breastfed infant from ZOKINVY or from the underlying maternal condition.

Data Lonafarnib is excreted in milk following oral administration in lactating rats, with a mean milk to plasma concentration ratio of 1.5 at 12 hours.

3. Females and Males of Reproductive Potential -                                             

Contraception ZOKINVY can cause embryo-fetal harm when administered to pregnant women .

Advise females of reproductive potential to use appropriate effective contraception during treatment with ZOKINVY.

Infertility- Based on findings in rats, ZOKINVY may reduce fertility in females and males of reproductive potential

4. Pediatric Use -                                                                                                          The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in pediatric patients 12 months of age and older.

Use of ZOKINVY for these indications is supported by adequate and well controlled studies in pediatric patients 2 years of age and older [see Clinical Studies

. The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.

6. Adult Use -                                                                                                                The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in adults.

Use of ZOKINVY in adults for these indications is based on adequate and well controlled studies in pediatric patients 2 years of age and older..