DRUG INTERACTIONS-

Midazolam (CYP3A4 substrate) In healthy subjects, concomitant administration of a single 8 mg oral dose of Moxidectin Tablets did not have an effect on the pharmacokinetics of midazolam 

Moxidectin can be co-administered with CYP3A4 substrates.

WARNINGS -

 • Cutaneous, Ophthalmological and/or Systemic Adverse Reactions of Varying Severity (Mazzotti Reaction):

This may occur in patients with onchocerciasis following treatment with Moxidectin Tablets.

Symptomatic Orthostatic Hypotension -Advise patients that if they feel dizzy, faint or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.

ADVERSE REACTIONS-

 The most common adverse reactions (incidence > 10%) were: eosinophilia, pruritus, musculoskeletal pain, headache, lymphopenia, tachycardia, rash, abdominal pain, hypotension, pyrexia, leukocytosis, influenza-like illness, neutropenia, cough, lymph node pain, dizziness, diarrhea, hyponatremia and peripheral swelling.

CONTRAINDICATIONS-

 None.

WARNINGS AND PRECAUTIONS-

 • Cutaneous, Ophthalmological and/or Systemic Adverse Reactions of Varying Severity (Mazzotti Reaction):

This may occur in patients with onchocerciasis following treatment with Moxidectin Tablets.

Monitor patients for symptoms, including symptomatic orthostatic hypotension.

 • Symptomatic Orthostatic Hypotension: Episodes of symptomatic orthostatic hypotension including inability to stand without support may occur in patients following treatment with Moxidectin Tablets.

 • Encephalopathy in Loa loa co-infected patients: Serious or even fatal encephalopathy following treatment with Moxidectin Tablets may occur in patients co-infected with Loa loa. Assess patients for loiasis in Loa loa endemic areas prior to treatment.

 • Edema and Worsening of Onchodermatitis: Patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe edema and aggravation of onchodermatitis.

PATIENT COUNSELING INFORMATION -

Signs and Symptoms Associated with Microfilarial Death

Advise patients that they are likely to have flu like symptoms including malaise, myalgia, headache, tachycardia, hypotension and pruritus, most commonly during the first week after treatment.

Symptomatic Orthostatic Hypotension -Advise patients that if they feel dizzy, faint or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.

Absence of Macrofilarial Activity -Advise patients that treatment with Moxidectin Tablets does not kill adult O. volvulus and that follow up evaluation is usually required.

Edema and Worsening of Onchodermatitis- Advise patients with hyper-reactive onchodermatitis that they may be more likely to experience severe adverse reactions.

Encephalopathy in Loa loa Co-infected Patients- Advise patients to report any symptoms of encephalopathy to their healthcare provider. Reference ID: 4277523 Page 12 of 12

Manufactured for: Medicines Development for Global Health, Melbourne, Victoria, Australia © 2018 Medicines Development for Global Health. All rights reserved

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                         Moxidectin, a macrocyclic lactone, is an anthelmintic drug..

2. Pharmacodynamics-                                                                                                 

Cardiac Electrophysiology- At a dose 4.5 times the approved recommended dose, moxidectin does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                      The pharmacokinetic parameters of moxidectin following a single 8 mg oral dose of Moxidectin Tablets to healthy subjects and patients with onchocerciasis under fasted conditions are shown in Table 4.

Mean moxidectin Cmax and AUC increased approximately proportionally to dose over a dose range of 2 to 36 mg (0.25 to 4.5 times the approved recommended dose) in healthy subjects under fasted conditions.

Table 4: Mean (± SD) Pharmacokinetic Parameters of Moxidectin Following a Single 8 mg

Oral Dose of Moxidectin Tablets to Healthy Subjects and Patients with Onchocerciasis Under Fasted Conditions PK Parameter Healthy Subjects (N = 27) Patients with Onchocerciasis (N = 31) Cmax (ng/mL) 58.9 ± 12.5 63.1 ± 20.0 Tmax* (hours) 4 (2, 8) 4 (1, 4) AUCinf (ng•h/mL) 3387 ± 1328 2738 ± 1606

Half-life (hours) 784 ± 347 559 ± 525 Cmax = maximum plasma concentration; Tmax = time to reach Cmax; AUCinf = area under the plasma concentration-time curve from time 0 to infinity; * Median (range)

Absorption- Effect of Food-

Moxidectin mean Cmax and AUC increased on average by 34% and 39%, respectively, when administered with a standard high fat meal (900 calories, with a nutritional distribution of approximately 55% fat, 31% carbohydrates and 14% protein), compared to fasted conditions .

Distribution-

The apparent mean ± SD volume of distribution of moxidectin is 2421 ± 1658 L in patients with onchocerciasis. The plasma protein binding in humans is unknown.

Elimination-

The mean terminal half-life of moxidectin in patients with onchocerciasis is 23.3 days (559 hours) following a single 8 mg dose of Moxidectin Tablets. The apparent mean ± SD total clearance of moxidectin is approximately 3.50 ± 1.23 L/hour in patients with onchocerciasis. 

Metabolism .-

The hepatic metabolism of moxidectin is minimal.

Excretion-

Following administration of a single 8 mg oral dose of Moxidectin Tablets to healthy subjects, 2% of the dose is eliminated unchanged in the feces within the first 72 hours. Renal elimination of intact drug is negligibl

Specific Populations-

In clinical studies, no clinically significant differences in the pharmacokinetics of moxidectin were observed based on age (18 to 60 years), sex, weight (42.7 to 107.2 kg), or renal impairment (creatinine clearance (CrCL) 47 to 89 mL/min, estimated by Cockcroft-Gault).

The pharmacokinetics of moxidectin in patients with CrCL less than 47 mL/min is unknown. The pharmacokinetics of moxidectin in patients with hepatic impairment is unknown.

Patients with Renal Impairment -

Based on a population pharmacokinetic analysis and the fact that renal elimination of intact drug is negligible, mild (creatinine clearance (CrCL), estimated by Cockcroft-Gault of 60 to 89 mL/min) and moderate (CrCL 30 to 59 mL/min) renal impairment is not likely to have an impact on the exposure of moxidectin.

The effect of severe renal impairment (CrCL 15 to 29 mL/min) or of end-stage renal disease on the pharmacokinetics of moxidectin is unknown.

Drug Interaction Studies-                                                                                                Clinical Study with Midazolam (CYP3A4 substrate) Co-administration of a single 8 mg dose of Moxidectin Tablets with a single oral 7.5 mg dose of midazolam (a sensitive CYP3A substrate) to healthy subjects (n = 37) did not affect the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy midazolam.

In Vitro Studies-

CYP Enzymes: Moxidectin is not a substrate or inhibitor of CYP enzymes. Uridine 5'-diphospho-glucuronosyltransferases (UGTs): Moxidectin is not a UGT substrate. Transporter Systems: Moxidectin is not a substrate of P-glycoprotein (P-gp) nor breast cancer resistance protein 1 (BCRP1).

 Microbiology-

 Mechanism of Action-                                                                                                      The mechanism by which moxidectin exhibits its effect against O. volvulus is not known. Studies with other nematodes suggest that moxidectin binds to glutamate-gated chloride channels (GluCl), gamma-aminobutyric acid (GABA) receptors and/or ATP-binding cassette (ABC) transporters.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summar-

Limited available data on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is a moxidectin-associated risk for major birth defects and miscarriage.

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%, 0respectively.

2. Lactation Risk Summary-

 Moxidectin was detected in the milk of lactating women following a single 8 mg dose of Moxidectin Tablets 

There are no data on the effects of Moxidectin Tablets on the breast-fed infant or milk production.

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

4. Pediatric Use The safety and effectiveness of Moxidectin Tablets have been established in pediatric patients 12 years of age and older. In Trial 1, (n = 53 patients aged 12 to 17 years), the safety and effectiveness was similar to that observed in adults .

The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.

5 Geriatric Use Of the total number of patients included in Trial 1 that were treated with Moxidectin Tablets, 83 were aged 65 and over.

No overall differences in safety or effectiveness were observed 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 o.

6. Renal Impairment No dose adjustment of Moxidectin Tablets is necessary for patients with mild (creatinine clearance (CrCL) 60 to 89 mL/min) to moderate (CrCL 30 to 59 mL/min) renal impairment.

The safety of Moxidectin Tablets in patients with severe renal impairment (CrCL 15 to 29 mL/min) or end stage renal disease, is unknown .

OVERDOSAGE-

 No specific antidote is available for overdose with Moxidectin Tablets. If overdose occurs, the patient should be monitored for evidence of toxicity.

Treatment of overdose with Moxidectin Tablets consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present.