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. 

BRIEF SUMMARY

MOXIDECTIN- (June 2018)

Indn-   To treat onchocerciasis due to Onchocerca Volvulus in patients aged 12 years and older

Comp-   Tablets: 2 mg.    Moxidectin is an anthelmintic indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older.  

ADR-  The most common adverse reactions  were: eosinophilia, pruritus, musculoskeletal pain, headache, lymphopenia, tachycardia, rash, abdominal pain, hypotension, pyrexia, leukocytosis, influenza-like illness, neutropenia, cough, lymph .

CI-   None.

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. Monitor patients for symptoms, including symptomatic orthostatic hypotension. 

Pat Inform-

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  16

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.

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. 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. 

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 negligible.

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).

 USE IN SPECIFIC POPULATIONS                                    

1.Pregnancy  Risk Summary-                                                                                             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%, respectively.

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.  

3.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 [see Adverse Reactions (6.1), and Clinical Studies (14)]. The safety and effectiveness of Moxidectin Tablets in pediatric patients under 12 years of age has not been established.

4.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 out

5.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.