BRIEF SUMMARY

DORAVIRINE -(Aug 2018)

Indn-             To  treat HIV-1 Infection in adult patients

Comp.       Tablets: 100 mg doravirine.  * Recommended dosage: One tablet taken orally once daily with or without food in adult patients.                                                                    Dosage adjustment with rifabutin: One tablet taken twice daily (approximately 12 hours apart).

ADR-   Most common adverse reactions (incidence greater than or equal to 5%, all grades) are nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams

CI-    * PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO.

 WARNINGS -

   Monitor for Immune Reconstitution Syndrome

Pat Inform-   

 Drug Interactions-                                                                                                             Inform patients that PIFELTRO may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort. 

For patients concomitantly receiving rifabutin, take one tablet of PIFELTRO twice daily (approximately 12 hours apart).

Immune Reconstitution Syndrome-                                                                                Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflamm

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  35

 ADVERSE REACTIONS-             

 Most common adverse reactions (incidence greater than or equal to 5%, all grades) are nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams

CONTRAINDICATIONS-   

 * PIFELTRO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO.

 WARNINGS AND PRECAUTIONS-

   Monitor for Immune Reconstitution Syndrome

PATIENT COUNSELING INFORMATION-

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

 Drug Interactions-                                                                                                             Inform patients that PIFELTRO may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort. 

For patients concomitantly receiving rifabutin, take one tablet of PIFELTRO twice daily (approximately 12 hours apart).

Immune Reconstitution Syndrome-                                                                                Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.

It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection.

Dosing Instructions-                                                                                                         Advise patients to take PIFELTRO every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance

 If a patient forgets to take PIFELTRO, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. 

Pregnancy Registry-                                                                                                          Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to PIFELTRO.

Lactation-                                                                                                                            Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

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 Copyright © 2018 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                     Doravirine is an antiretroviral drug

2. Pharmacodynamics-                                                                                                      In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of PIFELTRO, (in combination with FTC/TDF) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. 

Cardiac Electrophysiology -                                                                                               At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of PIFELTRO, doravirine does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                         Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects.

Specific Populations-                                                                                                         No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B).

The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown. 

Patients with Renal Impairment-                                                                                       In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment.

 In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.

Patients with Hepatic Impairment-                                                                                     No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).

Drug Interaction Studies-                                                                                                   Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine.

Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine.

Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. 

Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4.

Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K.

USE IN SPECIFIC POPULATIONS-   

1. Pregnancy-                                                                                                                       Pregnancy Exposure Registry-There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.  

Risk Summary- No adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures =8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO.

The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR.

 The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group.

2. Lactation-                                                                                                                     Risk Summary- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection.

 It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats.

Because of the potential for-                                                                                                 (1) HIV-1 transmission (in HIV-negative infants),                                                               (2) developing viral resistance (in HIVpositive infants), and                                                  (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PIFELTRO. 

4. Pediatric Use-                                                                                                                  Safety and efficacy of PIFELTRO have not been established in pediatric patients less than 18 years of age.

5. Geriatric Use -                                                                                                                  Clinical trials of PIFELTRO did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

In general, caution should be exercised in the administration of PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

6. Renal Impairment-                                                                                                           No dosage adjustment of PIFELTRO is required in patients with mild, moderate, or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients.

 7. Hepatic Impairment-                                                                                                     No dosage adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C)