DRUG INTERACTIONS-                                                                                           

1.Anticoagulant Drugs-                                                                                              Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage while also taking NUZYRA. 

 2.  Antacids and Iron Preparations A-bsorption of oral tetracyclines, including NUZYRA, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron containing preparations .

BRIEF SUMMARY

OMADACYLINE- (Oct 2018)

Indn-     To treat community-acquired bacterial pneumonia and  acute bacterial skin and skin structure infections

Comp-    For Injection: 100 mg of omadacycline (equivalent to 131 mg omadacycline tosylate) as a lyophilized powder in a single dose vial for reconstitution and further dilution before intravenous infusion                       

  Tablets: 150 mg omadacycline (equivalent to 196 mg omadacycline tosylate)

 is a tetracycline class antibacterial indicated for the treatment of adult patients with the following infections caused by susceptible microorganisms -

 Community-acquired bacterial pneumonia (CABP)

 Acute bacterial skin and skin structure infections (ABSSSI)

ADR-    The most common adverse reactions (incidence =2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation.

CI- Known hypersensitivity to omadacycline, tetracycline-class antibacterial drugs or any of the excipients in NUZYRA

WARNINGS-

 Mortality Imbalance in Patients with CABP: In the CABP trial, mortality rate of 2% was observed in NUZYRA-treated patients compared to 1% in moxifloxacin-treated patients. The cause of the mortality imbalance has not been established. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality.

Pat Inform-

 Allergic Reactions-                                                                                                             Advise patients-                                                                                                                 that allergic reactions, including serious allergic reactions, could occur and that serious allergic reactions require immediate treatment.  Ask the patient about any previous hypersensitivity reactions to NUZYRA, or other tetracycline class antibacterials.

 Administration with Food-                                                                                    Instruct patients to fast 4 hours before and 2 hours after taking NUZYRA tablets and not to consume dairy products, antacids, or multivitamins for 4 hours after taking NUZYRA tablets

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  43

ADVERSE REACTIONS-

 The most common adverse reactions (incidence =2%) are nausea, vomiting, infusion site reactions, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertension, headache, diarrhea, insomnia, and constipation.

CONTRAINDICATIONS-

  Known hypersensitivity to omadacycline, tetracycline-class antibacterial drugs or any of the excipients in NUZYRA

WARNINGS AND PRECAUTIONS-

 Mortality Imbalance in Patients with CABP: In the CABP trial, mortality rate of 2% was observed in NUZYRA-treated patients compared to 1% in moxifloxacin-treated patients. The cause of the mortality imbalance has not been established. Closely monitor clinical response to therapy in CABP patients, particularly in those at higher risk for mortality.

 Tooth Discoloration and Enamel Hypoplasia: The use of NUZYRA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown) and enamel hypoplasia.

 Inhibition of Bone Growth: The use of NUZYRA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth.

 Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs.

PATIENT COUNSELING INFORMATION-

 Nausea and Vomiting Advise patients that nausea and vomiting can be an adverse reaction to NUZYRA.  Advise patients that a greater proportion of patients who received the oral loading dose of NUZYRA for treatment of ABSSSI experienced nausea and vomiting.

 Allergic Reactions-                                                                                                             Advise patients-                                                                                                                 that allergic reactions, including serious allergic reactions, could occur and that serious allergic reactions require immediate treatment.  Ask the patient about any previous hypersensitivity reactions to NUZYRA, or other tetracycline class antibacterials.

 Administration with Food-                                                                                    Instruct patients to fast 4 hours before and 2 hours after taking NUZYRA tablets and not to consume dairy products, antacids, or multivitamins for 4 hours after taking NUZYRA tablets

 Tooth Discoloration and Inhibition of Bone Growth-                                                    Advise patients that NUZYRA, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. 

Tell your healthcare provider right away if you become pregnant during treatment

Lactation-                                                                                                                    Advise women not to breastfeed during treatment with NUZYRA and for 4 days after the last dose

 Diarrhea-                                                                                                                   Advise patients that diarrhea is a common problem caused by antibacterial drugs, including NUZYRA, which usually ends when the antibacterial drugs is discontinued.  Sometimes after starting treatment with antibacterial drugs, patients can develop watery or bloody stools (with or without stomach cramps and fever).  If this occurs, patients should contact their physician as soon as possible.

 Tetracycline Class Adverse Reactions-                                                                Inform patients that NUZYRA is similar to tetracycline-class antibacterial drugs and may have similar adverse reactions

 Antibacterial Resistance-                                                                                       Advise patients that antibacterial drugs including NUZYRA should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When NUZYRA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

 Skipping doses or not completing the full course of therapy may                                   (1) decrease the effectiveness of the immediate treatment  and                                    (2) increase the likelihood that bacteria will develop resistance and will not be treatable by NUZYRA or other antibacterial drugs in the future.

 Distributed by: 

 Paratek Pharmaceuticals, Inc.  Boston, MA, USA

 PARATEK® and the Hexagon Logo are registered trademarks of Paratek Pharmaceuticals, Inc. NUZYRA and its design logo are trademarks of Paratek Pharmaceuticals, Inc. For patent information: www.paratekpharma.com/product/patent. Copyright © 20

 CLINICAL PHARMACOLOGY-

1.  Mechanism of Action-                                                                                                                              NUZYRA is an antibacterial drug

2.  Pharmacodynamics-                                                                                                                                        Cardiac Electrophysiology-  Based on the nonclinical and clinical data, including electrocardiogram evaluation in the phase 3 clinical trials, one of which had moxifloxacin as a control group, no clinically relevant QTc prolongation was observed at the maximum recommended dose of omadacycline.

 Cardiac Physiology- Increase in Heart Rate  In phase 1 studies conducted in healthy volunteers, transient dose-dependent increases in heart rate have been observed following administration of single and multiple doses of omadacycline.

3. Pharmacokinetics-                                                                                                                                         The pharmacokinetic parameters of NUZYRA after single and multiple oral and intravenous doses are summarized.

Absorption-                                                                                                                                        Bioavailability 34.5% following single 300 mg dose of NUZYRA Tmax Median (min, max) Single dose 0.55 (0.25, 0.68) 2.50 (1, 4.05) 2.50 (1.5, 3) Steady state 0.50 (0, 1) 2.50 (0, 8) 2.50 (1.5, 4)

Distribution-                                                                                                                                                  Plasma Protein Binding 20%; not concentration dependent Volume of Distribution (L) Single dose 256 (25.6) 794 (23.6)b ND Steady state 190 (27.7) ND ND

 Elimination-                                                                                                                                                     Elimination Half-Life (hr) Single dose 16.2 (14.7) 14.96 (16.5) 13.45 (12.9) Steady state 16.0 (21.7) 15.5 (10.7) 16.83 (8.1) Systemic Clearance (L/hr) Single dose 11.24 (23.8) 34.6 (30.9)b ND Steady state 8.8 (25.2) ND ND Renal Clearance (L/hr) 2.4 to 3.3

 Metabolism-                                                                                                                                          Omadacycline is not metabolized

 Excretion-                                                                                                                                                         (Mean (SD) %dose) Urine 27(3.5) % 14.4 (2.3) %c ND Feces ND 81.1 (2.3) %c ND                                      a  All PK parameters presented as mean (% coefficient of variation; %CV) unless otherwise specified  b Presented as apparent clearance or volume of distribution                                                                        c Following administration of radiolabeled omadacycline  Cmax = maximum plasma concentration, AUC = area under concentration-time curve, IV = intravenous, ND = not determined, Tmax = time to Cmax Absorption The exposure to omadacycline is similar between a 300-mg oral dose and a 100-mg intravenous dose of NUZYRA in healthy fasted subjects. 

Effect of Food-                                                                                                                                              Ingestion of a standard high-fat nondairy meal (855 calories; 59% calories from fat) and standard high-fat meal including dairy (985 calories; 60% calories from fat) 2-hours before administration of a single 300-mg oral dose of NUZYRA decreased the rate (Cmax) and extent of absorption (AUC) by 40% and 42%, and 59% and 63%, respectively compared to administration of NUZYRA under fasting conditions.

The rate and extent of absorption of NUZYRA were not substantially decreased when a high-fat nondairy meal (800-1000 calories; 50% calories from fat) was ingested 4 hours pre-dose.  

 Following ingestion of either a light non-fat (300-350 calories; =5% calories from fat), or a standard low-fat (800-1000 calories; 30% calories from fat), or a standard high fat (800-1000 calories; 50% calories from fat) meal 2 hours post-dose, the AUC and Cmax were not substantially altered, as compared to fasting conditions.

 Distribution-                                                                                                                                                 Plasma protein binding of omadacycline is approximately 20% and is not concentration dependent.  The mean (% CV) volume of distribution of omadacycline at steady-state following IV administration of NUZYRA in healthy subjects was 190 (27.7) L.  

Elimination-                                                                                                                                                               Renal clearance of omadacycline following IV administration of NUZYRA ranged from 2.4 to 3.3 L/h in healthy subjects.  

Metabolism-                                                                                                                                                           In vitro studies using human liver microsomes and hepatocytes demonstrated that omadacycline is not metabolized. 

 Excretion-                                                                                                                                                          Following a 100-mg IV dose of NUZYRA, 27% of the dose was recovered as unchanged omadacycline in the urine.  In healthy male volunteers receiving 300-mg oral [14C] NUZYRA, 77.5% to 84.0% of the dose was recovered in the feces, approximately 14.4 % (range 10.8% to 17.4%) in the urine, with 95.5% of the administered radioactive dose recovered after 7 days.   

Specific Populations-                                                                                                         No clinically significant differences in the pharmacokinetics of omadacycline were observed based on age, gender, race, weight, renal impairment or end-stage renal disease, and hepatic impairment.  

Patients with Renal Impairment-                                                                                        A study was conducted to compare NUZYRA pharmacokinetics following 100-mg IV administration in 8 subjects with end-stage renal disease (ESRD) on stable hemodialysis, with and 8 -matched healthy control subjects. 

In the ESRD subjects, NUZYRA was administered on two separate occasions; immediately prior to dialysis and after dialysis, and the AUC, Cmax, and CL of NUZYRA were comparable between the renally impaired subjects and the matching healthy subjects.  During dialysis, 7.9% of omadacycline was recovered in the dialysate.

 Renal impairment did not impact NUZYRA elimination. 

Patients with Hepatic Impairment-

 A study was conducted to compare NUZYRA pharmacokinetics following intravenous and oral dosing to 5 subjects with mild hepatic impairment (Child-Pugh Class A), 6 subjects with moderate hepatic impairment (Child-Pugh Class B), and 6 subjects with severe hepatic impairment (Child-Pugh Class C) as compared to 12 matched healthy control subjects.  The AUC and Cmax of NUZYRA were comparable between the hepatically impaired subjects and the matching healthy subjects, and similar clearance was observed across all cohorts. 

Hepatic impairment did not impact NUZYRA elimination. 

 Drug Interaction Studies-

 Clinical Studies-                                                                                                Administration of oral verapamil (P-gp inhibitor) two hours prior to a single 300 mg oral dose of NUZYRA increased omadacycline AUC by approximately 25% and Cmax by approximately 9%.

In-vitro Studies In-vitro studies in human liver microsomes indicate that omadacycline does not inhibit nor induce metabolism mediated by CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, or UGT1A1.  Therefore, NUZYRA is not expected to alter the pharmacokinetics of drugs metabolized by the above stated human hepatic enzymes.

Omadacycline is not an inhibitor of P-gp and organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.

  Omadacycline is a substrate of P- gp (see Clinical Studies above).  Omadacycline is not a substrate or inhibitor of the major organic anion transporters (OAT-1 and 3), breast cancer resistance protein (BCRP), or multidrug resistance-associated protein 2 (MRP2).

 Omadacycline was not an OATP1B1 or OATP1B3 substrate at supra-therapeutic concentrations (5-13 fold higher than clinically relevant concentrations).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy                                                                                                                 Risk Summary- NUZYRA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy.

 The limited available data of NUZYRA use in pregnant women is insufficient to inform drug associated risk of major birth defects and miscarriages. 

Animal studies indicate that administration of omadacycline during the period of organogenesis resulted in fetal loss and/or congenital malformations in pregnant rats and rabbits at 7 times and 3 times the mean AUC exposure, respectively, of the clinical intravenous dose of 100-mg and the oral dose of 300-mg.

  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 15-20%.

 2. Lactation-                                                                                                                Risk Summary- There is no information on the presence of omadacycline in human milk, the effects on the breastfed infant or the effects on milk production.  Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including omadacycline, by the breastfed infant is not known. 

Because there are other antibacterial drug options available to treat CABP and ABSSSI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with NUZYRA and for 4 days (based on half-life) after the last dose. 

 3. Females and Males of Reproductive Potential                                      Contraception-                                                                                                     Females NUZYRA may produce embryonic or fetal harm.  Advise patients to use an acceptable form of contraception while taking NUZYRA.

Infertility -                                                                                                                             Males-                                                                                                                              In rat studies, injury to the testis and reduced sperm counts and motility occurred in male rats after treatment with omadacycline.

Females-                                                                                                                           In rat studies, omadacycline affected fertility parameters in female rats, resulting in reduced ovulation and increased embryonic loss at intended human exposures.

4. Pediatric Use-                                                                                                       Safety and effectiveness of NUZYRA in pediatric patients below the age of 18 years have not been established. 

Due to the adverse effects of the tetracycline-class of drugs, including NUZYRA on tooth development and bone growth, use of NUZYRA in pediatric patients less than 8 years of age is not recommended.

5. Geriatric Use-                                                                                                              Of the total number of patients who received NUZYRA in the Phase 3 clinical trials (n=1073), 200 patients were = 65 years of age, including 92 patients who were =75 years of age.  In Trial 1, numerically lower clinical success rates at early clinical response (ECR) timepoint for NUZYRAtreated and moxifloxacin-treated patients (75.5% and 78.7%, respectively) were observed in CABP patients = 65 years of age as compared to patients <65 years of age (85.2% and 86.3%, respectively). 

Additionally, all deaths in the CABP trial occurred in patients >65 years of age.           . No significant difference in NUZYRA exposure was observed between healthy elderly subjects and younger subjects following a single 100-mg IV dose of NUZYRA 

6. Hepatic Impairment-                                                                                                   No dose adjustment of NUZYRA is warranted in patients with mild, moderate, or severe hepatic insufficiency (Child-Pugh classes A, B, or C) 

7.  Renal Impairment-                                                                                                    No dose adjustment of NUZYRA is warranted in patients with mild, moderate, or severe renal impairment, including patients with end stage renal disease who are receiving hemodialysis 

 OVERDOSAGE-                                                                                                             No specific information is available on the treatment of overdosage with NUZYRA.  Following a 100 mg single dose intravenous administration of omadacycline, 8.9% of dose is recovered in the dialysate.