ATC codes:
P02CA01
EMLc
Indication
Other specified echinococcosis
ICD11 code:
1F73.Y
INN
Mebendazole
Medicine type
Chemical agent
List type
Complementary
Formulations
Oral > Solid:
500 mg tablet (chewable)
EML status history
First added in 2021
(TRS
1035)
Sex
All
Age
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Read more
about patents.
Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee acknowledged that diseases caused by taeniid cestode cysts (cystic echinococcosis, alveolar echinococcosis and neurocysticercosis) are neglected tropical diseases with a global disease burden for which a public health need exists for effective treatment.
The Committee noted that benzimidazoles are established as the treatment of choice for cystic echinococcosis and alveolar echinococcosis; anthelminthic therapy with albendazole or praziquantel is the treatment of choice for neurocysticercosis. These recommendations are supported by evidence for benefit from non-randomized and randomized clinical trials, expert consensus and in WHO and other international treatment guidelines. The Committee also noted that albendazole, mebendazole and praziquantel have been included on the Model Lists as anthelminthic treatments for other indications for more than 30 years, and their use in clinical practice is well established.
The Committee therefore recommended expanding the listings of albendazole, mebendazole and praziquantel on the EML and EMLc to include new indications for the diseases caused by taeniid cestode cysts. Specifically, albendazole and mebendazole for treatment of cystic echinococcosis and alveolar echinococcosis, and albendazole and praziquantel for treatment of neurocysticercosis. Noting the need for specialized diagnostic, monitoring and medical care for patients with these diseases, listing was recommended on the Complementary list, in a new sub-section for cysticidal medicines.
Background
Albendazole, mebendazole and praziquantel have not been previously considered for inclusion on the Model Lists for treatment of diseases caused by taeniid cestode cysts.
All three medicines are included on the Model Lists for other anthelminthic indications.
Public health relevance
Cystic echinococcosis
Human infection with Echinococcus granulosus leads to the development of one or more cysts located most often in the liver and lungs, and less frequently in the bones, kidneys, spleen, muscles and central nervous system. The asymptomatic incubation period of the disease can last many years until hydatid cysts grow large enough to trigger clinical signs. The clinical signs of E. granulosus infection vary depending on the number, location and size of the cysts. They and manifest commonly as pain and compromised organ function, which worsen as the cysts enlarge. Infection is debilitating and fatal in some patients. Cystic echinococcosis is globally distributed and is most prevalent in communities where pastoral activities predominate, as the most common transmission cycle involves dogs and sheep (but can also involve other livestock species). Such communities are found in all countries bordering the Mediterranean Sea, many regions and countries in central Asia, and parts of China, Australia and South America. In endemic regions, the incidence of cystic echinococcosis in humans can reach more than 50 per 100 000 person-years, and prevalence levels as high as 5–10% may occur in parts of Argentina, Central Asia, China, East Africa and Peru (1).
Alveolar echinococcosis
Infection in humans with E. multilocularis is characterized by an asymptomatic incubation period of 5–15 years and the slow development of a primary tumour-like lesion, which is usually located in the liver. Clinical signs include weight loss, abdominal pain, general malaise and signs of liver failure. Larval metastases may spread either to organs adjacent to the liver (for example, the spleen) or to distant locations (such as the lungs or the brain) by dissemination of the parasite via the blood and lymphatic system. If left untreated, alveolar echinococcosis is progressive and universally fatal. Alveolar echinococcosis is confined to the northern hemisphere, in particular to regions of China, the Russian Federation, Central Asia and countries in continental Europe.
Neurocysticercosis
Neurocysticercosis is caused by the larval stages of Taenia solium encysting in the central nervous system. In many cases, neurocysticercosis is asymptomatic, but the most common sign of symptomatic neurocysticercosis are epileptic seizures. Neurocysticercosis is thought to be the leading cause of preventable epilepsy worldwide. Neurocysticercosis can also cause chronic headaches, blindness, focal deficits and psychiatric symptoms. Clinical signs will vary depending on the number, location and size of the cysts. Parenchymal brain cysts are associated with seizures and epilepsy and are more amenable to treatment, particularly in individuals with viable or degenerating cysts. Extraparenchymal neurocysticercosis is associated with hydrocephalus, meningitis, focal neurological deficits, and sometimes death, and it is more difficult to treat. T. solium is endemic in South and Central America, South and South-East Asia, and parts of sub-Saharan Africa where pigs roam free (pigs are the intermediate host), and where open defecation is practised. It is a disease of poverty, principally affecting the most marginalized communities. Few data are available on the burden of disease caused by T. solium. Two different research groups estimated the number of epilepsy cases associated with neurocysticercosis globally to be 370 710 in 2010 (2) and 1.93 million in 2015 (3). WHO estimates the burden of T. solium to be 2 788 426 disability-adjusted life years (2). In areas endemic for cysticercosis, about 30% of people with epilepsy show lesions of neurocysticercosis on imaging (4).
Benefits
Cystic echinococcosis and alveolar echinococcosis
Benzimidazoles (albendazole and mebendazole) are indicated for patients with inoperable liver or lung cystic echinococcosis (patients with multiple cysts in two or more organs, or with peritoneal cysts). Small (< 5 cm) cystic echinococcosis 1 and cystic echinococcosis 3a cysts in the liver and lung respond well to benzimidazole alone. Benzimidazoles should be used to prevent recurrence following surgery, or puncture, aspiration, injection, reaspiration (PAIR) (5).
Albendazole is currently the drug of choice for cystic echinococcosis. Mebendazole may be used if albendazole is not available or not well tolerated. The standard dosage of albendazole of 10–15 mg/kg a day for 3–6 months has about a 30% cure rate. The number of patients with clinical or ultrasound improvement increases with longer durations of treatment while the proportion of patients with cure does not significantly change (6,7). Albendazole is more effective in young patients and for small cystic echinococcosis 1 and cystic echinococcosis 3a cysts. Benzimidazoles are less effective for cystic echinococcosis 2 and cystic echinococcosis 3b (6,7). The importance of cyst stage and size in determining response to treatment was confirmed by a systematic review (8). Sole treatment with a benzimidazole is also indicated for patients with inoperable liver or lung cystic echinococcosis; patients with multiple cysts in two or more organs and patients with peritoneal cysts. Drugs alone are not effective against giant cysts (> 10 cm in diameter) (9).
Benzimidazoles are also used as an adjunct to surgery or interventional procedures to: reduce the cyst’s internal tension; complement mechanical removal of the cyst or the chemical sterilization of the parasite; and prevent secondary echinococcosis (9). Albendazole in combination with PAIR has been shown to reduce the chance of cyst recurrence (10).
Benzimidazole treatment is required for several years in all patient with inoperable alveolar echinococcosis and following surgical resection of the parasite lesions. Since residual parasite tissue may remain undetected at radical surgery, including liver transplantation, benzimidazole should be given for at least 2 years and these patients should be monitored for a minimum of 10 years for possible recurrence. Presurgical benzimidazoles administration is not recommended except in the case of liver transplantation. Albendazole is the drug of choice for alveolar echinococcosis. Mebendazole may be given if albendazole is not available or not tolerated.
Controlled, but non-randomized, studies showed that long-term benzimidazole treatment improved the 10-year survival rate in patients with alveolar echinococcosis who had not had radical surgery compared with historical untreated control patients, from 6–25% to 80–83%, respectively (11), and prevented recurrences after radical surgery (12).
Neurocysticercosis
A meta-analysis of 11 randomized trials of albendazole and praziquantel for the treatment of neurocysticercosis evaluated the effect of cysticidal drugs on neuroimaging and clinical outcomes in 942 patients with neurocysticercosis (464 with cystic lesions, 478 with enhancing lesions) (13). Cysticidal drug therapy was associated with significantly higher rate of complete resolution of cystic lesions (44% versus 19%; P = 0.025) and with improved, though not statistically significant, resolution for enhancing lesions (72% versus 63%; P = 0.38). Excluding an outlier trial from the analysis, the difference in response for enhancing lesions became statistically significant (69% versus 55%; P = 0.006). The risk of seizure recurrence was lower after cysticidal treatment in patients with enhancing lesions (14% versus 37%; P = 0.001). The single trial evaluating the frequency of seizures in patients with cystic lesions showed a 67% reduction in the rate of generalized seizures with treatment (P = 0.006).
Harms
Albendazole, mebendazole and praziquantel have been used as treatments of choice for diseases caused by taeniid cestodes cysts for over 30 years.
Cystic echinococcosis and alveolar echinococcosis
Benzimidazoles are well tolerated in 70–80% of cases, but more adverse effects are seen in patients with immunosuppression (14). The most commonly reported side-effects are hepatotoxicity, elevation of aminotransferases, proteinuria, transient hair loss, gastrointestinal disturbances, leukopenia, thrombocytopenia and neurological symptoms, including sleeplessness and vertigo (15).
In cystic echinococcosis, benzimidazoles are contraindicated in cysts at risk of rupture and in early pregnancy. In addition, benzimidazoles must be used with caution in patients with chronic liver disease and avoided in patients with bone-marrow depression. In alveolar echinococcosis, due to the severity of the condition, contraindications are limited mainly to life-threatening side-effects (5).
For cystic echinococcosis, follow-up visits, including ultrasound examination should be performed every 3–6 months initially, and then annually once the situation is stable. Leukocyte counts and aminotransferase measurements are recommended at monthly intervals to monitor for adverse reactions (5). For alveolar echinococcosis, monitoring of liver enzymes and blood cell counts are recommended every 2 weeks for the first 3 months, then monthly for 1 year, then every 3 months. Decreased leukocyte count below 1 x 10^9/L indicates benzimidazole toxicity and warrants treatment withdrawal (5).
Neurocysticercosis
The main side-effects of albendazole in patients treated with doses of 15 mg/kg a day or lower for 28 days are due to parasiticidal activity and treatment-induced inflammation and include headaches, seizures and dizziness. There is a transient increase in the number of seizures after therapy. Hepatotoxicity and leukopenia are known adverse effects of albendazole and are considered relative contraindications to continued use. Monitoring of liver enzymes and complete blood counts is recommended during the first month of treatment (16).
Randomized trials of albendazole for neurocysticercosis have found no significant differences in adverse events between patients treated with albendazole or placebo (17,18).
The main side-effects of praziquantel in patients with neurocysticercosis are due to its cysticidal activity, and include headache, dizziness and seizures. Doses up to 100 mg/kg a day for up to 28 days have been used in neurocysticercosis without additional laboratory adverse effects. More than 10% of patients treated with praziquantel experience gastrointestinal side-effects including nausea, vomiting and abdominal pain. As with albendazole therapy, monitoring of liver enzymes and complete blood counts is recommended (16).
Cost / cost effectiveness
The cost of albendazole (400 mg tablets) varies widely. The cost of 3 months of treatment for cystic echinococcosis in endemic countries for generic or locally produced albendazole ranges from US$ 39.60 in Turkey to US$ 987.30 in Chile.
For the minimum 14-day treatment of neurocysticercosis in endemic countries, the cost for generic or locally produced albendazole ranges from US$ 10.50 in Zambia to US$ 39.50 in Uganda. For praziquantel, the 14-day treatment costs range from US$ 16.80 in Uganda to US$ 132.30 in Mexico.
Mebendazole tablets are donated to WHO from the manufacturer.
WHO guidelines
WHO guidelines for the management of T. solium neurocysticercosis were approved (with revisions) by the WHO Guidelines Review Committee in October 2020.
The guideline includes two proposed recommendations on antiparasitic treatment.
Recommendation 1: Anthelminthic therapy in combination with corticosteroids should be provided to individuals with symptomatic neurocysticercosis and viable parenchymal brain cysts for better outcomes in terms of cyst resolution, and potentially improved seizure control (strong recommendation, moderate quality of evidence).
Rationale: The quality of evidence was moderate for the effect of anthelminthic therapy on cyst resolution, and for the effect of anthelminthic therapy in improving seizure control. It was decided that this should be a strong recommendation because the potential benefit – cyst resolution and possibly improved seizure control – likely outweighs any potential harm associated with the use of anthelminthic therapy.
Remarks:
• Albendazole, in combination with corticosteroids, has been shown to be superior to either corticosteroids only or no treatment at all.
• Dual therapy with praziquantel and albendazole has been shown to be more effective than treatment with albendazole alone in individuals with two or more parenchymal brain cysts.
• Evidence on the use of albendazole in pregnant women was not evaluated; pregnant women should seek expert advice before receiving treatment with albendazole.
• There is no evidence that anthelminthic therapy in children should be different to that of adults.
• Although evidence is lacking, the clinical experience of experts indicates that anthelminthic drugs should not be used in patients with symptomatic neurocysticercosis and encephalitis. If inflammation is pronounced in these cases, patients should be treated with corticosteroids alone.
• Enhanced dosing schedules of corticosteroids (i.e. of 28 days duration) were associated with better clinical outcomes compared with shorter dosing schedules (e.g. of 10 days duration); however, this may not be the optimal schedule.
Recommendation 2: Anthelminthic therapy in combination with corticosteroids should be provided to individuals with symptomatic neurocysticercosis and a single enhancing lesion for better outcomes in terms of cyst resolution and potentially improved seizure control (moderate recommendation, moderate to very low quality of evidence).
Rationale: The quality of evidence was considered low for the effect of anthelminthic therapy on cyst resolution, and very low for the effect of anthelminthic therapy in improving seizure control. It was decided that this should be a conditional recommendation because of the methodological differences between studies. However, all studies found the combination of albendazole and corticosteroids to have a beneficial effect.
Remarks:
• Many studies are available on the use of anthelminthic therapy in combination with corticosteroids in individuals with a single enhancing lesion; however, significant limitations are present in the synthesis of these data in existing meta-analyses.
The application included a summarized version of the evidence on which these recommendations were based. Notably, only studies related to albendazole were included, because the studies that included praziquantel had methodological problems (19–21). However, based on expert opinion, and a study of the combination of albendazole and praziquantel (22), praziquantel was also included in the recommendation.
Availability
Albendazole 400 mg tablets are available in originator and generic brands.
Mebendazole 500 mg tablets are available in originator and generic brands. WHO receives donation of 500 mg mebendazole tablets from Johnson & Johnson.
Praziquantel 500 mg and 600 mg tablets are produced by Merck. Praziquantel 600 mg tablets are also produced by Bayer, and donated to WHO for the treatment of T. solium taeniasis.
Other considerations
Comments on the application were received from Médecins Sans Frontières, in which strong support for the proposed listings was expressed.
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