Artesunate (artesunate)

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Artesunate is administered as a slow IV bolus. The drug is supplied in a single-dose vial as a powder that must be constituted with the supplied diluent prior to administration. After constitution, administer the solution IV (through an established IV line or needle).

Do not administer artesunate via continuous IV infusion. Artesunate has been administered IM+ in clinical studies and is included as an alternate route of administration in WHO guidelines for the treatment of severe malaria in adults and children.

Administer artesunate with an antimalarial agent that is active against the hypnozoite liver stage forms of Plasmodiumto patients with severe malaria due to P. vivax or P. ovale.

Store vials of artesunate for injection and sterile diluent in the carton at <=30degreesC. Do not freeze. Avoid exposure to heat. Keep protected from light. Do not use beyond the expiration date.

Administer the constituted solution within 1.5 hours of constitution with the supplied diluent.

Artesunate and its metabolite, dihydroartemisinin (DHA), are not metabolized to any significant extent by cytochrome P-450 (CYP)1A2, 2D6, 2C19, 2A6, 2E1, or 3A. Artesunate is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4/5. DHA is a weak inhibitor of CYP1A2 and 2C19. No dosage adjustments are needed for inhibitors or inducers of these enzymes when co-administered with artesunate.

DHA is a substrate of UDP-glucuronosyltransferase (UDP-UGT) 1A9 and UGT2B7. DHA is not a substrate or inhibitor of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Artesunate is a substrate of BCRP and P-gp. Artesunate is a weak inhibitor of organic anion transporting polypeptide (OATP) 1B1 and organic anion transporter (OAT) 3.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Artesunate/Strong Ugt Inducers; Nevirapine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase (UGT) and nevirapine may increase the metabolism of dihydroartemisinin (DHA, the active metabolite of artesunate).(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine, efavirenz, etravirine, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, or ritonavir may result in decreased levels and effectiveness of DHA.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If coadministration of strong UGT inducers or nevirapine with artesunate is necessary, monitor for possible reduced antimalarial efficacy.(1)

DISCUSSION: In a study, nevirapine decreased the maximum concentration (Cmax) and area-under-curve (AUC) of DHA by 59% and 68%, respectively.(1) In a study of healthy volunteers, ritonavir (100 mg twice daily for 7 days) decreased the Cmax and AUC of DHA by 27% and 38%, respectively.(1,2) A study of healthy subjects who were coadministered lopinavir-ritonavir 400 mg-100 mg twice daily for 14 days) and artesunate-mefloquine found that artesunate Cmax and AUC decreased by 37% and 45%, respectively, compared to artesunate-mefloquine alone.(3) Agents linked to this monograph include: carbamazepine, efavirenz, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.

Selected Weak Cyp2d6 Inhibitors/Tamoxifen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of weak CYP2D6 inhibitors should be closely monitored.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, cimetidine, clobazam, clomipramine, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sarpogrelate, sertraline, verapamil and viloxazine.(29)

Weak Cyp2d6 Inhibitors/Eliglustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP3A4 and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The dosage of eliglustat with weak inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with weak inhibitors of CYP2D6 in extensive CYP2D6 metabolizers with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, chlorpromazine, clobazam, clomipramine, desvenlafaxine, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, felodipine, gefitinib, hydralazine, hydroxychloroquine, lorcaserin, methadone, panobinostat, propafenone, sarpogrelate, sertraline, vemurafenib, and venlafaxine.(3,4)

*Known serious hypersensitivity to artesunate, such as anaphylaxis.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• No disease contraindications

The most common adverse reactions (incidence of >=2%) reported with IV artesunate in clinical trials of severe malaria include acute renal failure requiring dialysis, hemoglobinuria, and jaundice.

More Frequent

• Acute renal failure
• Jaundice

Less Frequent

• Abnormal hepatic function tests
• Acute respiratory distress syndrome
• Anemia
• Disseminated intravascular coagulation
• Hyperbilirubinemia
• Leukocytosis
• Lymphopenia
• Neutropenic disorder
• Pneumonia
• Pulmonary edema
• Thrombocytopenic disorder

Rare or Very Rare

• Anaphylaxis
• Autoimmune hemolytic anemia
• Hypersensitivity drug reaction
• Leukopenia
• Pancreatitis
• Stevens-johnson syndrome

More Frequent

• Hemoglobinuria

Less Frequent

• Acute cognitive impairment
• Ataxia
• Diarrhea
• General weakness
• Hemiplegia
• Nervousness
• Tremor

Rare or Very Rare

• Acute abdominal pain
• Cough
• Dizziness
• Dysgeusia
• Fever
• Headache disorder
• Skin rash
• Tinnitus
• Urticaria
• Vomiting

No enhanced messaging available.

The safety and effectiveness of artesunate for the treatment of severe malaria have been established in pediatric patients. Use of artesunate 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 6 months of age and older.

For pediatric patients younger than 6 months of age, a pharmacokinetic extrapolation approach using modeling and simulation indicated comparable or higher predicted 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. No notable safety issues were identified in limited published safety and outcome data for artesunate in pediatric patients younger than 6 months of age with severe malaria. No dose adjustment is necessary for pediatric patients regardless of age or bodyweight.

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. Pregnancy outcomes reported from a study with IV artesunate are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or fetal death. Experience with oral artesunate+ and other artemisinin class drugs (via various routes of administration) in pregnant women over several decades, based on published literature from randomized controlled trials and cohort studies, have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The bioavailability of oral artesunate+ is expected to be significantly lower than IV artesunate; therefore, the clinical relevance of studies involving oral exposure to artesunate and other artemisinin class drugs is uncertain.

Animal reproduction studies show that a single IV administration of artesunate to rats early in gestation results in embryolethality. Although animal reproduction studies in several species have demonstrated fetal harm from oral and IV administered artesunate and other artemisinin class drugs, the clinical relevance of these animal data is uncertain.

There is a pregnancy safety study for artesunate. If artesunate is administered during pregnancy, healthcare providers should report artesunate exposure by contacting Amivas LLC at1-855-526-4827 (1-855-5AMIVAS) or https://amivas.com/.

Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirth, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.

Dihydroartemisinin (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 and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical studies of artesunate did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger patients.