DRUG INTERACTIONS-(summary)

 Co-administration of PAXLOVID can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PAXLOVID.

Consider the potential for drug interactions prior to and during PAXLOVID therapy and review concomitant medications during PAXLOVID therapy. 

DRUG INTERACTIONS- (details)

1. Digoxin There is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg. Patients taking INPEFA with concomitant digoxin should be monitored appropriately 

2. Uridine 5'-diphospho-glucuronosyltransferase (UGT) Inducer Glucuronidation by UGT1A9, to form the 3-O-glucuronide, was identified as a major metabolic pathway for sotagliflozin.

The coadministration of rifampicin, an inducer of UGTs, with a single dose of 400 mg sotagliflozin resulted in a decrease in the exposure to sotagliflozin. This decrease in exposure to sotagliflozin may decrease efficacy [see Clinical Pharmacology (12.3)].

3.Lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and dosage changes.

BRIEF SUMMARY

NIRMATRELVIR- (May 2023)

Indication-   Treat mild-to-moderate COVID -19    in adults at high risk for progression                                                                       

Dosage-   Treat mild-to-moderate COVID -19   in adults at high risk for progression to severe condition

ADR-  Most common adverse reactions are dysgeusia and diarrhea.

CI- Co-administration with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations with  potential for loss of virologic response and resistance.

 Pat inform-  Inform patients that interaction with certain drugs and is contraindicated for use  advise patients to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products .i

Inform patients that anaphylaxis, serious skin reactions, and other hypersensitivity reactions have been reported.

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 20

Name-                          PAXLOVID

Acive  Ingredient -      NIMATRELVIR/ RITONAVIR

Pharmacological clssificiation-        To  Treat mild-to-moderate COVID -19                                                                             in adults at high risk for progression to                                                                          severe COVID-19                                                                                                                                              

 Date of Approval-         5/25/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                          PAXLOVID safely and effectively.

See full prescribing information for PAXLOVID. PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets), co-packaged for oral use

Initial U.S. Approval: 2023

WARNING:

SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID See full prescribing information for complete boxed warning.

• PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater xposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events.

 • Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, nterruption, and/or additional monitoring.

 • Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drugdrug interactions for an individual patient can be appropriately managed.

 INDICATIONS AND USAGE-

 PAXLOVID which includes nirmatrelvir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

 Limitations of Use PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19.

DOSAGE AND ADMINISTRATION-

 PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. (2.1) Nirmatrelvir must be co-administered with ritonavir.

 • Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.

 • Administer orally with or without food.

 • Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days.

 • Dose reduction for moderate renal impairment (eGFR =30 to <60 mL/min): 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both tablets taken together twice daily for 5 days.

 • PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min). 

 ADVERSE REACTIONS-

 Most common adverse reactions (incidence =1% and greater incidence than in the placebo group) are dysgeusia and diarrhea.

 CONTRAINDICATIONS-

 • History of clinically significant hypersensitivity reactions to the active ingredients (nirmatrelvir or ritonavir) or any other components.

• Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

 • Co-administration with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.

 WARNINGS AND PRECAUTIONS-

 • The concomitant use of PAXLOVID and certain other drugs may result in potentially significant drug interactions. Consult the Full Prescribing Information prior to and during treatment for potential drug interactions.

 • Hypersensitivity Reactions: Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID.

If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.

 • Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir.

 • HIV-1 Drug Resistance: PAXLOVID use may lead to a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

DOSAGE AND ADMINISTRATION-

 PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. (2.1) Nirmatrelvir must be co-administered with ritonavir.

 • Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.

 • Administer orally with or without food.

 • Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days.

 • Dose reduction for moderate renal impairment (eGFR =30 to <60 mL/min): 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both tablets taken together twice daily for 5 days.

 • PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min). 

• PAXLOVID is not recommend in patients with severe hepatic impairment (Child-Pugh Class C).

 DOSAGE FORMS AND STRENGTHS-

 • Tablets: nirmatrelvir 150 mg

 • Tablets: ritonavir 100 mg

PATIENT COUNSELING INFORMATION

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

Drug Interactions Inform patients that PAXLOVID may interact with certain drugs and is contraindicated for use with certain drugs; therefore, advise patients to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].

Hypersensitivity Reactions Inform patients that anaphylaxis, serious skin reactions, and other hypersensitivity reactions have been reported, even following a single dose of PAXLOVID. A

dvise them to immediately discontinue the drug and to inform their healthcare provider at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction [see Warnings and Precautions (5.2)]. Reference ID: 5178484 34 Dosage

Modification in Patients with Moderate Renal Impairment To ensure appropriate dosing in patients with moderate renal impairment, instruct such patients that they will be taking one 150 mg nirmatrelvir tablet with one 100 mg ritonavir tablet together twice daily for 5 days [see Dosage and Administration (2.3)].

Administration Instructions Inform patients to take PAXLOVID with or without food as instructed.

Advise patients to swallow all tablets for PAXLOVID whole and not to chew, break, or crush the tablets.

Alert the patient of the importance of completing the full 5-day treatment course and to continuing isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of SARS-CoV-2.

If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule.

If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time.

The patient should not double the dose to make up for a missed dose [see Dosage and Administration (2)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For Medical Information about PAXLOVID, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-1523-0.12

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4)]. Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

2. Pharmacodynamics-

Cardiac Electrophysiology At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics-

The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19. Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir.

Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects Nirmatrelvir (When Given With Ritonavir) Ritonavir Absorption Tmax (hr), median 3.00a 3.98a

Food effect Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinf and Cmax for nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively. b Distribution % bound to human plasma proteins 69% 98-99% Blood-to-plasma ratio 0.60 0.14d Vz/F (L), mean 104.7c 112.4c

Elimination Major route of elimination Renal eliminationd

Hepatic metabolism Half-life (T½) (hr), mean 6.05a 6.15a Oral clearance (CL/F) (L/hr), mean 8.99c 13.92c

Metabolism- Metabolic pathways Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal. Major CYP3A, Minor CYP2D6

Excretion % drug-related material in feces 35.3%e 86.4%f % of dose excreted as total (unchanged drug) in feces 27.5%e 33.8%f % drug-related material in urine 49.6%e 11.3%f % of dose excreted as total (unchanged drug) in urine.

.

Effect of Food No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1000 calories; 50% fat) to healthy subjects.

Specific Populations There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity. Pediatric Patients The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.

Patients with Renal Impairment The pharmacokinetics of nirmatrelvir in patients with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. 

Patients with Hepatic Impairment The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg.

The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary Based on animal data showing renal effects, INPEFA is not recommended during the second and third trimesters of pregnancy.

Available data with INPEFA in pregnant women are insufficient to evaluate for a drugassociated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with untreated heart failure in pregnancy

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.

.2. Lactation Risk Summary-

There are no data on the presence of INPEFA in human milk, the effects on the breastfed infant, or the effects on milk production. Sotagliflozin is present in rat milk..

3.Pediatric Use The safety and effectiveness of INPEFA in pediatric patients under 18 years of age have not been established.

4. Geriatric Use-

No INPEFA dosage change is recommended based on age. In the SOLOIST study, a total of 241 (40%) patients treated with INPEFA were between 65 and < 75 years of age, and 174 (29%) were = 75 years of age. In the SCORED study, a total of 2,470 (47%) patients treated with INPEFA were between 65 and < 75 years of age, and 1,240 (23%) were = 75 years of age.

No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension. In patients = 65 years of age, a higher proportion of patients treated with INPEFA had adverse reactions of volume depletion.

5. Renal Impairment-

 INPEFA was evaluated in 5,292 patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2 ) in the SCORED study and in 426 patients with heart failure with eGFR < 60 mL/min/1.73 m2 in the SOLOIST study.

The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR < 30 mL/min/1.73 m2 relative to the overall safety population.

Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. After starting therapy in these studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 or were initiated on chronic dialysis.

6. Hepatic Impairment

In a clinical pharmacology study in patients with hepatic impairment, the exposure in mild hepatic impairment was not increased, but was approximately 3-fold as high in moderate and approximately 6-fold as high in severely hepatic-impaired subjects compared to subjects with normal hepatic function.

No dosage adjustment is necessary in patients with mild hepatic impairment.

The safety and efficacy of INPEFA have not been established in patients with moderate or severe hepatic impairment.

10 OVERDOSAGE -

There were no confirmed reports of symptomatic overdose with sotagliflozin during the clinical development program of INPEFA. In the event of an overdose with INPEFA, contact the Poison Control Center. Employ the usual supportive measures as dictated by the patient’s clinical status. The removal of sotagliflozin by hemodialysis has not been studied.

11 DESCRIPTION INPEFA tablets for oral administration contain sotagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The chemical name of sotagliflozin is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 6-(methylthio)tet