Ivermectin

In vitro studies have shown that ivermectin is primarily metabolised by CYP3A4. Consequently, caution is advised when ivermectin is administered concomitantly with potent CYP3A4 inhibitors as the plasma exposure may be significantly increased.

Concomitant treatment with diethylcarbamazine citrate (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 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 onchoceriasis 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 (oedema and aggravation of onchodermatitis).

During mass treatment of onchocerciasis, data on a limited number (approximately 300) of pregnant women indicated no adverse effects such as congenital anomalies, spontaneous abortions, stillbirths and infant mortality which might be associated with ivermectin treatment during the first trimester of pregnancy. To date, no other epidemiological data are available.

Animal studies have shown reproductive toxicity; however, the predictive value of these observations has not been established.

Ivermectin should only be used when strictly indicated.

There are no or a limited amount of data from the topical use of ivermectin in pregnant women.

Following oral administration, less than 2% of the administered dose of ivermectin appears in breast milk. Safety of use has not been established in newborn infants. Ivermectin may only be given to breastfeeding mothers if the expected benefit outweighs the potential risk to the infant.

Excretion in human milk following topical administration has not been evaluated.

Fertility

No human data on the effect of ivermectin on fertility are available. In rats, there was no effect on mating or fertility with ivermectin treatment.

The effect of ivermectin on the ability to drive and use machines has not been studied. The possibility in some patients of side effects such as dizziness, somnolence, vertigo and tremor, which may affect the ability to drive or use machines, cannot be excluded.

Oral administration

Transient hypereosinophilia, liver dysfunction including acute hepatitis, increased liver enzymes, hyperbilirubinemia and haematuria have been reported.

Very rarely, toxic epidermal necrolysis and Stevens-Johnson syndrome have also been reported.

Side effects are related to the parasite density and are mild and transient in the majority of cases, but their severity may be increased in patients infected with more than one parasite, particularly in the case of infestation with Loa loa.

Rarely, severe and potentially fatal cases of encephalopathy have been described following administration of ivermectin, particularly in patients also heavily infected with Loa loa. In these patients, the following adverse reactions have also been reported: back or neck pain, ocular hyperaemia, subconjunctival haemorrhage, dyspnoea, urinary and/or faecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor or coma.

In patients receiving ivermectin for the treatment of strongyloidiasis, the following adverse reactions have been reported: asthenia, abdominal pain, anorexia, constipation, diarrhoea, nausea, vomiting, dizziness, somnolence, vertigo, tremor, transient hypereosinophilia, leukopenia/anaemia and increase in ALAT/alkaline phosphatases. In the treatment of Wuchereria bancrofti filariasis, the intensity of undesirable effects does not seem to be dose-dependent but is related to the microfilarial density in blood. The following have been described: fever, headache, asthenia, feeling of weakness, myalgia, arthralgia, diffuse pain, digestive disorders such as anorexia, nausea, abdominal and epigastric pain, cough, feeling of respiratory discomfort, sore throat, orthostatic hypotension, chills, vertigo, profuse sweating, testicular pain or feeling of discomfort.

Following administration of ivermectin in patients infected with Onchocerca volvulus, the hypersensitivity reactions observed resulting from microfilarial death pertain to Mazzotti-type reactions: pruritus, urticarial rash, conjunctivitis, arthralgia, myalgia (including abdominal myalgia), fever, oedema, lymphadenitis, adenopathies, nausea, vomiting, diarrhoea, orthostatic hypotension, vertigo, tachycardia, asthenia, headache. Rarely, these symptoms have been severe. A few cases of asthma exacerbation have been described. In these patients, abnormal sensation in the eyes, eyelid oedema, anterior uveitis, conjunctivitis, limbitis, keratitis and chorioretinitis or choroiditis have also been described. These manifestations, which may be due to the disease itself, have also been described occasionally after treatment. They were rarely severe and generally resolved without corticosteroid treatment.

Onset of conjunctival haemorrhage has been reported in patients with onchocerciasis. Observations of adult Ascaris expulsion have been described following ingestion of ivermectin.

In patients with scabies, transient exacerbation of pruritus may be observed at the start of treatment.

Topical application

Summary of the safety profile

The most commonly reported adverse reactions are skin burning sensation, skin irritation, pruritus and dry skin, all occurring in 1% or less of patients treated with the medicinal product in clinical trials.

They are typically mild to moderate in severity, and usually decrease when treatment is continued.

No meaningful differences in the safety profile were observed between subjects 18 to 65 years and subjects ≥65 years of age.

List of adverse reactions

The adverse reactions are classified by System Organ Class and frequency, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data) and were reported with Soolantra in clinical studies.

Skin and subcutaneous tissue disorders

Common: Skin burning sensation

Uncommon: Skin irritation, pruritus, dry skin, Rosacea aggravation*

Not known: Erythema, dermatitis contact (allergic or irritant), swelling face

Investigations

Not known: Transaminases increased*

* Adverse reaction reported from post-marketing data.