DRUG INTERACTIONS-summary

Nevirapine or ritonavir antiretrovirals If used concomitantly, monitor for Strong UGT inducers (e.g., possible reduced antimalarial efficacy. rifampin, carbamazepine,

DRUG INTERACTIONS-details

1. Effect of Other Drugs on Artesunate and Dihydroartemisinin (DHA) Ritonavir, Nevirapine or Strong UDP-Glucuronosyltransferase (UGT) Inducers:

Published clinical reports or in vitro reports indicate that concomitant use of Artesunate for Injection with oral ritonavir, nevirapine, or UGT inducers may decrease dihydroartemisinin (DHA) AUC and Cmax which may reduce the efficacy of Artesunate for Injection.

If Artesunate for Injection is co-administered with ritonavir, nevirapine or strong UGT inducers (e.g., rifampin, carbamazepine, phenytoin), monitor for possible reduced antimalarial efficacy of Artesunate for Injection.

Strong UGT Inhibitors Published reports of in vitro data indicate that concomitant use of Artesunate for Injection with UGT inhibitors may increase DHA AUC and Cmax, which may increase DHA associated adverse reactions.

Monitor for adverse reactions when co-administering Artesunate for Injection with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac). 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  21

ADVERSE REACTIONS

­ The most common adverse reactions (incidence of 2% or greater) reported with Artesunate for Injection in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice. 

CONTRAINDICATIONS-

Serious hypersensitivity to artesunate, such as anaphylaxis. 

WARNINGS AND PRECAUTIONS-

­ • Post-treatment Hemolysis: Cases of post-treatment hemolytic anemia severe enough to require transfusion have been reported. Monitor patients for 4 weeks after treatment for evidence of hemolytic anemia.

 • Hypersensitivity: Serious hypersensitivity reactions including anaphylaxis have been reported. Discontinue if signs of serious hypersensitivity occur.

PATIENT COUNSELING INFORMATION-                                                                        Additional Antimalarial Treatment-                                                                                   Advise patients of the need to complete appropriate oral antimalarial therapy after treatment with Artesunate for Injection 

. Advise patients of the need to take an additional antimalarial agent such as an 8-aminoquinoline drug during or after treatment with Artesunate for Injection for P. vivax/P. ovale malaria to prevent relapse

 Post-treatment Hemolysis -                                                                                                   Advise patients of the need for regular blood tests for the 4-week period following completion of Artesunate for Injection to monitor for post-treatment delayed hemolysis

 Hypersensitivity Reactions and Anaphylaxis -                                                                   Inform patients that hypersensitivity reactions, including anaphylaxis, have occurred with administration of Artesunate for Injection.

Inform patients of the signs and symptoms of hypersensitivity reactions and anaphylaxis and instruct patients to seek immediate medical care if they experience such symptoms during or following administration of Artesunate for Injection

Embryo-Fetal Toxicity in Animals-                                                                                            Advise pregnant patients and patients who could be pregnant of the potential drug-related embryo-fetal toxicity based on animal studies and the serious risks to mother and fetus of delaying treatment for severe malaria.

Instruct patients to inform their healthcare provider of a known or suspected pregnancy

Advise women who are exposed to Artesunate for Injection during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes.

Encourage these patients to report their pregnancy to Amivas LLC at 1-855-526-4827 (1-855-5AMIVAS) or www.amivas.com/our-products

Manufactured for Amivas LLC 1209 Orange St Wilmington Delaware 19801 USA 20190530

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-

Artesunate is an antimalarial drug [see Microbiology (12.4)].

2. Pharmacodynamics-                                                                                               Artesunate and DHA exposure-response relationships and their time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology-                                                                                                    At the approved intravenous dose of 2.4 mg/kg Artesunate for Injection, artesunate and DHA do not cause large mean increases (i.e., 20 msec) in the QTc interval.

3. Pharmacokinetics-                                                                                                              Following administration of 2.4 mg/kg Artesunate for Injection, artesunate is rapidly converted to DHA by blood esterases. The PK parameters of artesunate (AS) and DHA in patients with severe malaria following administration of multiple doses of 2.4 mg/kg Artesunate for Injection are -

 Summary of Median (Range) Pharmacokinetic Parameters in Patients with Severe Malaria (N=14) PK Parameter AS DHA Cmax (mcg/mL) 3.3 (1.0-164) 3.1 (1.7-9.5) AUC (mcg-h/mL) 0.7 (0.3-111.3) 3.5 (2.2-6.3)

Distribution -                                                                                                                       Volume of Distribution (L) 68.5 (0.2-818) 59.7 (26-117) Protein Binding Approximately 93%

Elimination -                                                                                                                              Half-life (hours) 0.3 (0.1-1.8) 1.3 (0.9-2.9) Clearance (L/h) 180 (1-652) 32.3 (16-55)

In vitro Metabolism-                                                                                                                    Primary Pathway Blood Esterases Glucuronidation Metabolite DHA a-DHA-ß-glucuronide

Excretion-                                                                                                                               Urine Unknown Unknown PK=pharmacokinetics, AS=artesunate, DHA=dihydroartemisinin, Cmax=maximum concentration, AUC=area under the concentration-time curve

Specific Populations -                                                                                                           Pediatric: PK simulations, using a published population-based meta-analysis of DHA PK indicate a dosing regimen of 2.4 mg/kg results in comparable or greater predicted steady-state DHA AUC0-12 in infants less than 6 month of age compared to that observed in older children or adults 

Clinical Drug-Drug Interaction Studies -                                                                        Nevirapine: Co-administration of oral artesunate with nevirapine resulted in a decrease in Cmax and AUC of DHA by 59% and 68%, respectively. This reduction in systemic PK exposure of DHA is also likely to occur with Artesunate for Injection and may result in the potential loss of antimalarial efficacy.

Ritonavir: Co-administration of oral artesunate with ritonavir resulted in a 27% and 38% decrease in Cmax and AUC, respectively of DHA. This reduction in systemic PK exposure of DHA is also likely to occur with Artesunate for Injection and may result in the potential loss of antimalarial efficacy.

Other Anti-Malarial Drugs: No clinically significant drug interactions were reported with co-administration of oral artesunate with atovaquone/proguanil, mefloquine, amodiaquine and sulfadoxine/pyrimethamine.

Therefore, drug interactions between Artesunate for Injection and these drugs are not expected.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary There are serious risks to the mother and fetus associated with untreated severe malaria during pregnancy; delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus.

.The bioavailability of oral artesunate is expected to be significantly lower than intravenous artesunate; therefore, the clinical relevance of studies involving oral exposure to artesunate and other artemisinin class drugs is uncertain.

The estimated background risk of miscarriage and maternal and fetal death for the indicated population is higher than the general population.

The estimated background risk of major birth defects for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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                                                                                                      DHA, a metabolite of artesunate, is present in human milk. There are no data on the effects of artesunate or DHA on the breastfed infant or on milk production.

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

3. Pediatric Use-                                                                                                                      The safety and effectiveness of Artesunate for Injection for the treatment of severe malaria have been established in pediatric patients.

Use of Artesunate for Injection for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged 6 months and older .

For pediatric patients younger than 6 months of age, a pharmacokinetic (PK) extrapolation approach using modeling and simulation indicated comparable or higher predicted PK steady-state AUC of DHA between this age group and older children or adults at the recommended 2.4 mg/kg dose regimen of Artesunate for Injection.

4.Geriatric Use-                                                                                                                           Clinical studies of Artesunate for Injection did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. 

5. Renal Impairment-                                                                                                                    No specific PK studies have been carried out in patients with renal impairment. Most patients with severe malaria present with some degree of related renal impairment. No specific dosage adjustments are needed for patients with renal impairment.

6. Hepatic Impairment-                                                                                                                No specific PK studies have been carried out in patients with hepatic impairment. Most patients with severe malaria present with some degree of related hepatic impairment. No specific dose adjustments are needed for patients with hepatic impairment.

 OVERDOSAGE

Experience of acute overdose with artesunate is limited.

A case of artesunate overdose has been documented in a 5-year-old child inadvertently administered rectal artesunate at a dose of 88 mg/kg/day (approximately 18 times the maximum recommended daily dose for Artesunate for Injection) for 4 days.

Artesunate for Injection is not approved for rectal administration. The overdose was associated with pancytopenia, melena, seizures, multiorgan failure and death. Treatment of overdose should consist of general supportive measures.