4.1. Therapeutic indications

• Treatment of intestinal strongyloidiasis (anguillulosis).

• Treatment of proven or suspected microfilaremia in patients with lymphatic filariasis caused by Wuchereria bancrofti.

• Treatment of human sarcoptic scabies. Treatment is justified when the diagnosis of scabies has been established clinically and/or by parasitological examination. Without formal diagnosis treatment is not justified in case of pruritus.

Official guidelines should be taken into consideration. Official guidelines will normally include WHO and public health authorities' guidelines.

4.2. Posology and method of administration

Posology

Treatment of intestinal strongyloidiasis

The recommended dosage is one single oral dose of 200 micrograms of ivermectin per kg body weight.

For guidance, the dose, as determined by the patient's weight, is as follows:

BODY WEIGHT (kg)

DOSE

Number of 3 mg tablets

15 to 24

one

25 to 35

two

36 to 50

three

51 to 65

four

66 to 79

five

≥ 80

six

Treatment of microfilaremia caused by Wuchereria bancrofti

The recommended dosage for mass distribution for the treatment of microfilaremia caused by Wuchereria bancrofti is a single oral dose once every 6 months designed to provide approximately 150 to 200 μg/kg of body weight.

In endemic areas where treatment can only be administered once every 12 months, the recommended dosage is 300 to 400 μg/kg of body weight to maintain adequate suppression of microfilaremia in treated patients.

For guidance, the dose, as determined by the patient's weight, is as follows:

BODY WEIGHT (kg)

DOSE when given once every 6 months Number of 3 mg tablets

DOSE when given once every 12 months

Number of 3 mg tablets

15 to 25

one

two

26 to 44

two

four

45 to 64

three

six

65 to 84

four

eight

Alternatively and if no scales are available, the dose of ivermectin for use in mass chemotherapy campaigns may be determined by the patient's height as follows:

HEIGHT (cm)

DOSE when given once every 6 months

Number of 3 mg tablets

DOSE when given once every 12 months Number of 3 mg tablets

90 to 119

one

two

120 to 140

two

four

141 to 158

three

six

> 158

four

eight

Treatment of human sarcoptic scabies

The recommended dosage is a single oral dose to provide ivermectin 200 μg/kg body weight.

Common scabies

Recovery will be considered as definite only after 4 weeks of treatment. Persistence of pruritus or scraping lesions does not justify a second treatment before this date.

Administration of a second dose within 2 weeks after the initial dose should only be considered:

a) when new specific lesions occur

b) when the parasitologic examination is positive at this date.

Profuse and crusting scabies:

In these heavily infected forms, a second dose within 8 to 15 days of ivermectin and/or concomitant topical therapy may be necessary to obtain recovery.

For all indications, safety in pediatric patients weighing less than 15 kg of body weight has not been established.

Method of administration

Oral route.

In children less than 6 years of age, tablets should be crushed before swallowing.

Treatment is one single oral dose taken with water on an empty stomach.

The dose may be taken at any time of the day, but no food should be taken within two hours before or after administration, as the influence of food on absorption is unknown.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Special warnings

Efficacy and dosing regimen of ivermectin in immunocompromised patients being treated for intestinal strongyloidiasis have not been established by adequate clinical studies. There have been reported cases which show the persistence of infestation following a single dose of ivermectin particularly in this type of patients.

Ivermectin is not a prophylactic therapy of infection with filariae or anguillulosis; there are no data available demonstrating the efficacy of ivermectin either for killing or preventing the maturation of infective larvae in humans.

Ivermectin has not been shown to have any activity against the adult worm of any species of Filariae.

Ivermectin has not been shown to have any beneficial effect on tropical pulmonary eosinophilia syndrome on lymphadenitis or lymphangitis observed in case of infection with filariae.

Following administration of ivermectin, the intensity and severity of adverse experiences are probably related to the pretreatment microfilarial density particularly in the blood. In patients co-infected with Loa loa, microfilarial density, particularly in the blood, is most often high which predisposes the treated patients to an increased risk in the occurrence of serious adverse experiences.

CNS adverse experiences (encephalopathies) have been rarely reported in patients treated with ivermectin and co-infected by a high number of microfilariae of Loa loa. Consequently, in Loa loa endemic areas, special measures should be taken before any treatment with ivermectin (see section 4.8).

Neurological toxicity, including depressed level of consciousness and coma, has also been reported in patients with the use of ivermectin in the absence of Loa loa infection. These events have generally resolved with supportive care and the discontinuation of ivermectin. (See sections 4.8 and 4.9).

Concomitant treatment with DEC and ivermectin in mass chemotherapy campaigns for filariasis caused by Wuchereria Bancrofti in Africa is not recommended. Co-infection with other microfilariae, such as Loa loa may result in high microfilaraemia in patients infected.

Systemic exposure to DEC in such patients may result in the occurrence of serious side effects related to the rapid and effective microfilaricidal effects of this drug.

Following administration of drugs with a rapid microfilaricidal action such as diethylcarbamazine citrate (DEC) in patients with onchocerciasis, cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction), and ophthalmological reactions have been reported.

These reactions are probably due to inflammatory responses to degradation products released following the death of microfilariae.

Patients treated with ivermectin for onchocerciasis may also experience these reactions when treated for the first time. After treatment with a microfilaricidal drug, patients with hyperreactive onchodermatitis or “Sowda” (observed particularly in Yemen) may be more likely than others to experience severe cutaneous adverse reactions (edema and aggravation of onchodermatitis).

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported with ivermectin treatment (see section 4.8).

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, ivermectin should be withdrawn immediately and an alternative treatment considered. If the patient has developed a severe cutaneous adverse reaction such as SJS or TEN with the use of ivermectin, treatment with ivermectin must not be restarted at any time.

In the absence of convincing evidence of efficacy (and safety) for use of ivermectin as a treatment for COVID-19 it is strongly recommended that ivermectin is not used for the treatment of patients with or suspected to be infected with SARS-COV2 as this may lead to a delay in diagnosis and /or receiving appropriate treatment for COVID-19. The extent and risks of such use will be monitored as part of the risk management plan.

Precautions for use

Safety in paediatric patients weighing less than 15 kg of body weight has not been established.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

Data on a limited number (approximately 300) of exposed pregnancies in mass treatment campaigns for onchocerciasis, indicate no adverse effects, like congenital anomalies, spontaneous abortions, fetal deaths/stillbirths and infant mortalities , after ivermectin use in the first trimester. To date, no other epidemiological data are available.

Animal studies have shown reproductive toxicity (see section 5.3); however, the potential risk for humans is unknown.

Ivermectin should only be used when strictly indicated.

Breastfeeding

Less than 2% of the administered dose of ivermectin appears in breast milk.

Safety in newborn infants has not been established: therefore, the drug should be given to nursing mothers only if the benefit to the mother outweighs the potential risk to the breast-fed infant, and treatment of mothers who intend to breast feed their infants should be delayed until 1 week after birth of the child.

4.7. Effects on ability to drive and use machines

It is not known if ivermectin has an influence on the ability to drive and use machines. Possible side effects such as dizziness, somnolence, vertigo and tremor, may affect some patients' ability to drive or operate machinery (see section 4.8).

4.8. Undesirable effects

Side effects are related to the microfilarial density and most of them are mild and transient in nature but the incidence and severity may be higher in patients infected with more than one parasite, as in the case of infection with Loa loa.

Rarely, patients who are also heavily infected with Loa loa may develop serious or even fatal encephalopathy following treatment with ivermectin.

In the treatment of filariasis caused by Wuchereria bancrofti, the intensity of the side effects does not seem to be dose-related but is related to the blood microfilarial density.

Following treatment of patients infected with Onchocerca volvulus with ivermectin, the following hypersensitivity reactions may occur due to the death of microfilariae: these are symptoms of Mazzotti type reactions: pruritus, frank urticarial rash, conjunctivitis, arthralgia, myalgia (including abdominal myalgia), fever, edema, lymphadenitis, lymphadenopathies, nausea, vomiting, diarrhea, orthostatic hypotension, vertigo, tachycardia, asthenia, headache. These reactions have been rarely severe. Some cases of worsening of bronchial asthma have been reported.

In these patients, abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis and chorioretinitis or choroiditis, have also been described. These reactions can occur due to the disease itself, but have also occasionally been reported after theraphy. These have rarely been severe and have generally resolved without corticosteroid treatment.

Cases of ascaris expulsion of adult worms have been described following administration of ivermectin. In patients with scabies, transient exacerbation of pruritus may be noted at the beginning of treatment.

Tabulated list of adverse reactions

Table 1: Adverse Reactions with Ivermectin

MedDRA System Organ Class

Frequency

Adverse Reaction(s)

Blood and lymphatic system disorders

Not known

Transient eosinophilia, leukopaenia/anaemia1

Metabolism and nutrition disorders

Not known

Anorexia1, 2

Psychiatric disorders

Not known

Mental status changes3

Nervous system disorders

Not known

Encephalopathy3, depressed level of consciousness, somnolence1, vertigo1, 2, tremor1, dizziness1, postural hypotension2, coma, confusion3, stupor3, headache2, lethargy3, difficulty in standing3

Eye disorders

Not known

Ocular hyperaemia3, conjunctival haemorrhage3, 4

Respiratory, thoracic and mediastinal disorders

Not known

Cough2, sore throat2, dyspnoea2,3

Gastrointestinal disorders

Not known

Abdominal pain1, 2, constipation1, diarrhoea1, vomiting1, nausea1, 2, epigastric pain2, fecal incontinence3

Hepatobiliary disorders

Not known

Hepatitis acute, hyperbilirubinemia

Skin and subcutaneous tissue disorders

Very rare

Toxic epidermal necrolysis, Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders

Not known

Myalgia2, arthralgia2, back pain3, neck pain3

Renal and urinary disorders

Not known

Urinary incontinence3, haematuria

Reproductive system and breast disorders

Not known

Testicular pain2, testicular discomfort2

General disorders and administration site conditions

Not known

Fever2, chills2, diaphoresis2, asthenia1, 2, body pain2, difficulty in walking3

Investigations

Not known

Elevated liver enzymes, alanine aminotransferase increased1, alkaline phosphatase increased1

1In the treatment of strongyloidiasis

2In the treatment of filariasis caused by Wuchereria bancrofti

3In the treatment of patients who are heavily infected with Loa Loa

4In the treatment of patients with onchocerciasis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

It is important to adhere to recommended dosages. Cases of depressed level of consciousness and coma have been reported with overdosage of ivermectin.

In cases of accidental intoxication with unknown quantities of veterinary formulations of ivermectin in humans, either by ingestion, injection, exposure to body surfaces, the following symptoms have been reported: rash, contact dermatitis, edema, headache, vertigo, asthenia, nausea, vomiting, diarrhea and abdominal pain. Other adverse effects that have been reported, include: seizures, ataxia, dyspnea, paresthesia, and urticaria.

Management in case of accidental poisoning:

- symptomatic treatment and supervision in specialised care unit with fluid replacement and hypertensive treatment if necessary. Although there are no data available, it seems advisable to avoid the use of GABA agonists in the treatment of accidental intoxications due to ivermectin.