MOXIDECTIN- moxidectin tablet
Medicines Development for Global Health
1 INDICATIONS AND USAGE
Moxidectin Tablets are indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older [ see Clinical Studies ( 14) ].
Limitations of Use:
Moxidectin Tablets do not kill adult O . volvulus. Follow-up evaluation is advised.
The safety and efficacy of repeat administration of Moxidectin Tablets in patients with O . volvulus has not been studied.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Patients Aged 12 Years and Older
The recommended dosage of Moxidectin Tablet is a single dose of 8 mg (four 2 mg tablets) taken orally with or without food [see Clinical Pharmacology ( 12.3)].
3 DOSAGE FORMS AND STRENGTHS
Moxidectin Tablets are available as white to pale yellow uncoated oval-shaped tablets, debossed on one side with “AKKA”. Each tablet contains 2 mg of moxidectin.
5 WARNINGS AND PRECAUTIONS
5.1 Cutaneous, Ophthalmological and/ or Systemic Adverse Reactions
Treatment with Moxidectin Tablets may cause cutaneous, ophthalmological and/or systemic reactions of varying severity (Mazzotti reaction). These adverse reactions are due to allergic and inflammatory host responses to the death of microfilariae [see Adverse Reactions ( 6.1)]. There is a trend toward an increased incidence of these adverse reactions in patients with higher microfilarial burden.
The clinical manifestations of Mazzotti reaction includes pruritus, headache, pyrexia, rash, urticaria, hypotension (including symptomatic orthostatic hypotension and dizziness) [ see Warnings and Precautions ( 5.2)] , tachycardia, edema, lymphadenopathy, arthralgia, myalgia, chills, paresthesia and asthenia. Ophthalmological manifestations include conjunctivitis, eye pain, eye pruritus, eyelid swelling, blurred vision, photophobia, changes in visual acuity, hyperemia, ocular discomfort and watery eyes. These adverse reactions generally occur and resolve in the first week post-treatment. Laboratory changes include eosinophilia, eosinopenia, lymphocytopenia, neutropenia, and increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH). Proteinuria has also been reported.
Treatment of severe Mazzotti reactions has not been evaluated in controlled clinical trials. Symptomatic treatments such as oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat orthostatic hypotension. Antihistamines and/or analgesics have been used for most mild to moderate cases.
5.2 Symptomatic Orthostatic Hypotension
An increased number of patients who received Moxidectin Tablets developed symptomatic orthostatic hypotension with inability to stand without support after lying down for 5 minutes (in an orthostatic hypotension provocation test); 47/978 (5%) compared with 8/494 (2%) who received ivermectin. The decreases in blood pressure were transient, managed by resumption of recumbency and most commonly occurred on Days 1 and 2 post-treatment. Advise patients that if they feel dizzy or light-headed after taking Moxidectin Tablets, they should lie down until the symptoms resolve.
5.3 Encephalopathy in Loa loa Co – infected Patients
Patients with onchocerciasis who are also infected with Loa loa may develop a serious or even fatal encephalopathy following treatment with Moxidectin Tablets.
Moxidectin Tablets have not been studied in patients co-infected with Loa loa. Therefore, it is recommended that individuals who warrant treatment with Moxidectin Tablets and have had exposure to Loa loa -endemic areas undergo diagnostic screening for loiasis prior to treatment.
5.4 Edema and Worsening of Onchodermatitis
Patients with hyper-reactive onchodermatitis (sowda) may be more likely than others to experience severe edema and worsening of onchodermatitis following the use of Moxidectin Tablets. Symptomatic treatment has been used to manage patients who have experienced edema and worsening of onchodermatitis.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described in greater detail in other labeling sections:
- Cutaneous, Ophthalmological and/or Systemic Adverse Reactions
[see Warnings and Precautio ns ( 5.1)]
- Symptomatic Orthostatic Hypotension
[see Warnings and Precautions ( 5.2)]
- Encephalopathy in Loa loa Co-infection [see Warnings and Precautions ( 5.3)]
- Edema and Worsening of Onchodermatitis [see Warnings and Precautions ( 5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under varying controlled conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of Moxidectin Tablets was evaluated in two randomized, double-blind, active-controlled studies (Trial 1 and Trial 2) [see Clinical Studies ( 14)]. In Trial 1, 978 patients received Moxidectin Tablets as a single oral dose of 8 mg and 494 patients received ivermectin as a single oral dose of approximately 150 mcg/kg. In Trial 2, 127 patients received Moxidectin Tablets as a single oral dose ranging from 2 mg (this is not an approved dose) to 8 mg (38 received the recommended 8 mg dose) and 45 patients received ivermectin as a single oral dose of approximately 150 mcg/kg.
Most Common Adverse Reactions
No patients withdrew from either trial due to adverse reactions. Adverse Reactions reported in Trial 1 in > 10% of patients are summarized in Table 1. Most were related to physical, vital signs and laboratory changes associated with Mazzotti reaction [see Warnings and Precautions ( 5.1)].
|Adverse Reaction||Moxidectin N = 978 n (%)||Ivermectin N = 494 n (%)|
|Eosinophilia||721 (74)||390 (79)|
|Pruritus||640 (65)||268 (54)|
|Musculoskeletal pain a||623 (64)||257 (52)|
|Headache||566 (58)||267 (54)|
|Lymphocytopenia*||470 (48)||215 (44)|
|Tachycardia b||382 (39)||148(30)|
|Orthostatic tachycardia c||333 (34)||130 (26)|
|Non-orthostatic tachycardia d||179 (18)||57 (12)|
|Rash e||358 (37)||103 (21)|
|Abdominal pain f||305 (31)||173 (35)|
|Hypotension g||289 (30)||125 (25)|
|Orthostatic hypotension h||212 (22)||81 (16)|
|Pyrexia/Chills||268 (27)||88 (18)|
|Leukocytosis||240 (25)||125 (25)|
|Influenza like illness||226 (23)||102 (21)|
|Neutropenia**||197 (20)||112 (23)|
|Cough||168 (17)||88 (18)|
|Lymph node pain||129 (13)||28 (6)|
|Dizziness||121 (12)||44 (9)|
|Diarrhea/Gastroenteritis/Enteritis||144 (15)||84 (17)|
|Hyponatremia||112 (12)||65 (13)|
|Peripheral swelling||107 (11)||30 (6)|
a Includes “myalgia”, “arthralgia”, “musculoskeletal pain”, “pain” and “back pain”
b Includes “orthostatic heart rate increased”, “postural orthostatic tachycardia syndrome”, “heart rate increased” and “sinus tachycardia”
c Includes “orthostatic heart rate increased” and “postural orthostatic tachycardia syndrome”
d Includes “heart rate increased”, “tachycardia”, and “sinus tachycardia”
e Includes “rash,” “papular rash” and “urticaria”
f Includes “abdominal pain”, “abdominal pain upper” and “abdominal pain lower”
g Includes “orthostatic hypotension”, “blood pressure orthostatic decreased”, “blood pressure decreased”, “mean arterial pressure decreased”, “hypotension”
h Includes “orthostatic hypotension”, and “blood pressure orthostatic decreased”
*Lymphocytopenia is defined as absolute lymphocyte count less than 1 x 10 9 /L
**Neutropenia is defined as absolute neutrophil count less than 1 x 10 9 /L
The most common adverse reactions in patients (n = 38) treated with 8 mg moxidectin in Trial 2 were similar to the adverse reactions noted in Trial 1 described in Table 1 above.
Other Adverse Reactions Reported in Clinical Trials
The following adverse reactions occurred in less than 10% of subjects receiving Moxidectin Tablets in Trial 1:
Ocular Adverse Reactions : In Trial 1, the most common ocular adverse reactions (occurring in ≥ 0.5% of patients) is shown in Table 2.
|Adverse Reaction||Moxidectin N = 978 n ( % )||Ivermectin N = 494 n ( % )|
|Eye pain||78 (8)||28 (6)|
|Eye pruritus||64 (7)||26 (5)|
|Visual impairment*||25 (3)||9 (2)|
|Eyelid edema||21 (2)||5 (1)|
|Conjunctivitis allergic||19 (2)||11 (2)|
|Ocular discomfort**||18 (2)||11 (2)|
|Ocular and conjunctival hyperemia||17 (2)||3 (1)|
|Lacrimation increased||13 (1)||10 (2)|
*Includes “visual impairment”, “blurred vision” and “low vision acuity”
**Includes “foreign body sensation”, “ocular discomfort” and “abnormal sensation in the eye”
Hepatobiliary Adverse Reactions
More patients in the moxidectin arm experienced elevation in bilirubin above the upper limit of normal and elevation in transaminases > 5x upper limit of normal. Twenty-seven (2.8%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had hyperbilirubinemia. Most of the patients had single measurements of hyperbilirubinemia without concurrent elevation in transaminases.
Nine (1%) patients in the moxidectin arm and 2 (0.4%) patients in the ivermectin arm had elevation in ALT of more than 5x upper limit of normal; ten (1%) patients in the moxidectin arm and 3 (0.6%) patients in the ivermectin arm had elevation in AST to more than 5x upper limit of normal.
Laboratory abnormalities occurring in at least 1% of patients in the Trial 1 are described in Table 3.
|Parameter||MOXIDECTIN ( N = 978) n (%)||Ivermectin ( N = 494) n (%)|
|Severe eosinophilia (> 5 x10 9 /L)||173 (18)||111 (23)|
|Grade 3 lymphocytopenia (< 0.5 x10 9 /L)||220 (23)||98 (20)|
|Grade 4 Neutrophils (< 0.5 x10 9 /L)||65 (7)||46 (9)|
|Eosinopenia (<0.045 x10 9 /L)||51 (5)||21 (4)|
|GGT (> 5x upper limit of normal)||26 (3)||16 (3)|
|Bilirubin (> 2x upper limit of normal)||14 (1.4)||2 (0.4)|
|AST (> 5x upper limit of normal)||10 (1)||3 (0.6)|
|ALT (> 5x upper limit of normal)||9 (1)||2 (0.4)|
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