Biltricide (Praziquantel)

Praziquantel is a synthetic anthelmintic that is structurally unrelated to other anthelmintic medicines currently available.

Praziquantel (Biltricide) uses

Trematode (fluke) infections

Schistosomiasis

Praziquantel is used to treat schistosomiasis (bilharzia) caused by all Schistosoma species that infect humans. The medicine has been used effectively both for individual patients and in mass-treatment and control programs.

Praziquantel is effective against all stages of Schistosoma infection, including acute and chronic disease, which may involve the liver and spleen. The medicine appears to be effective in severe schistosomiasis (for example, neuroschistosomiasis). To help prevent major illness and long-term complications associated with this condition, such as paraplegia and persistent impotence, treatment with praziquantel needs to start promptly. Treatment may be started in patients with suspected neuroschistosomiasis while confirmatory test results are still pending.

Adult schistosomes do not multiply inside the human body, so the worm burden depends on how intense and frequent the infection is and how long the worms live. Mature schistosomes constantly produce eggs, most of which remain trapped in body tissues, triggering an immune granulomatous response as well as tissue damage and scarring. How severe the disease becomes is linked to the intensity of infection. Antischistosomal medicines work by greatly reducing the worm burden and therefore stopping further egg production.

Praziquantel has produced cure rates of 75-95% and/or egg reduction rates of 80-98% in patients with schistosomiasis and is considered the medicine of choice for infections caused by Schistosoma (S.) haematobium, S. japonicum, S. mansoni, or S. mekongi. It is the only anthelmintic currently available that has been shown to be effective for infections caused by S. intercalatum or S. mekongi. Oxamniquine is considered an alternative to praziquantel for infections caused by S. mansoni, although it is not generally commercially available in Australia. Use of niridazole or antimony salts for S. japonicum infections has been replaced by praziquantel because of lower toxicity and better effectiveness.

The effectiveness of praziquantel in schistosomiasis may vary depending on the patient's age and the severity of infection. Cure rates are generally lower in children and in patients with heavy infections.

Travellers

Travellers to endemic areas of the Caribbean, South America, Africa and Asia are at risk of schistosomiasis. Because there is no practical way for travellers to tell infested water from non-infested water, freshwater swimming in rural areas of endemic countries should be avoided. Outbreaks of schistosomiasis have occurred among adventure travellers taking part in river trips in Africa, as well as among expatriates and Peace Corps volunteers living in high-risk areas.

Those at greatest risk are travellers who wade, swim or bathe in freshwater in areas with poor sanitation and suitable snail hosts. To reduce the risk of illness caused by delayed recognition of schistosomal infection, Australian travel health guidance supports serologic screening for travellers and expatriates with a history of freshwater exposure (for example, recreational exposure) returning from Schistosoma-endemic areas. After a thorough clinical assessment, seropositive individuals should receive praziquantel treatment.

Neuroschistosomiasis should be considered in anyone with central nervous system (CNS) abnormalities who has returned from endemic areas. These infections can develop several months after exposure to infested water, and eggs may be undetectable or hard to identify in urine and stool. Presumptive treatment with praziquantel should be started promptly whenever there is a strong suspicion of infection and should not be delayed while waiting for confirmatory tests.

Clonorchiasis and opisthorchiasis

Praziquantel is used to treat clonorchiasis caused by Clonorchis sinensis (Chinese liver fluke) and opisthorchiasis caused by Opisthorchis viverrini (South-East Asian liver fluke). Praziquantel has produced cure rates of 86-98% in patients with clonorchiasis or opisthorchiasis and is currently considered the medicine of choice for treating these infections.

Other trematode infections

Praziquantel has also been used effectively to treat other trematode (fluke) infections caused by Paragonimus westermani (lung fluke), Metagonimus yokogawai (intestinal fluke), Nanophyetus salmincola (formerly Troglotrema salmincola) (intestinal fluke), Heterophyes heterophyes (intestinal fluke), Fasciolopsis buski (intestinal fluke), and Metorchis conjunctus (North American liver fluke), and it is currently considered the medicine of choice for these infections.

Praziquantel has been used in a limited number of patients for infections caused by Fasciola hepatica (sheep liver fluke), but the medicine was inactive against the trematode in vitro in one study and treatment failures have been reported. For that reason, other medicines, such as bithionol or triclabendazole [drugs not generally commercially available in Australia], are preferred for these infections. Praziquantel has also been effective in a limited number of patients with infections caused by P. kellicotti (American lung fluke), P. heterotrema (lung fluke), and P. uterobilateralis (African lung fluke).

Cestode (tapeworm) infections

Praziquantel has been used to treat cestodiasis (tapeworm infections) caused by certain cestodes that infect humans, including Diphyllobothrium latum (fish tapeworm), Dipylidium caninum (dog and cat tapeworm), Taenia saginata (beef tapeworm), and T. solium (pork tapeworm).

Praziquantel or niclosamide (not generally commercially available in Australia) is currently considered the medicine of choice for infections caused by these cestodes. Praziquantel has also been used to treat infections caused by Hymenolepis nana (dwarf tapeworm) and is currently considered the medicine of choice for these infections.

Praziquantel is effective against the adult, juvenile and larval stages of these cestodes. Although niclosamide and paromomycin are effective for cestodiasis caused by T. solium, some clinicians consider praziquantel the medicine of choice because niclosamide and paromomycin break up worm segments and release viable eggs. This may carry a theoretical risk of cysticercosis developing; niclosamide is not effective against cysticerci.

Praziquantel has also been used effectively to treat cysticercosis caused by Cysticercus cellulosae (the larval or tissue stage of T. solium), and praziquantel or albendazole is currently considered the medicine of choice for this infection.

Although praziquantel has been effective for adult Echinococcus infections in dogs, studies in rodents and sheep have failed to show any benefit in larval Echinococcus infections (hydatid cysts). It is therefore unlikely that these infections in humans will respond to the medicine. Surgical removal of the cysts or, when surgery is contraindicated or cysts rupture spontaneously during surgery, mebendazole or albendazole is currently considered the treatment of choice.

Because praziquantel can kill Echinococcus (for example, protoscoleces), it may be useful for perioperative prophylaxis or if cyst contents are spilled during surgery.

Praziquantel has been used effectively, preferably together with corticosteroids, to treat neurocysticercosis caused by T. solium. In a limited number of patients, praziquantel treatment has been shown to produce a long-term reduction in seizure frequency and in how often and how severely episodes of raised intracranial pressure occur. It has also produced radiographic evidence of fewer and smaller cysts.

Because nervous system side effects (cerebrospinal fluid (CSF) reaction syndrome) occur frequently during praziquantel treatment for neurocysticercosis, more research is needed to fully determine the balance of benefit and risk in this condition. Occasionally, ventricular shunting for hydrocephalus and, rarely, surgical removal of cysts (for example, in the ventricles and/or basal cisterns) may be necessary.

Most clinicians recommend using corticosteroids at the same time as praziquantel in patients with neurocysticercosis to reduce how often these praziquantel-related nervous system side effects occur and how severe they are.

Patients receiving praziquantel for neurocysticercosis usually need to stay in hospital for the duration of treatment. Because praziquantel-induced CSF reaction syndrome may be more dangerous in patients with spinal cysticercosis than in other forms of neurocysticercosis, some clinicians have recommended that the medicine not be used to manage this condition. Spinal cysticercosis generally requires surgery to relieve spinal cord dysfunction caused by compression or an intramedullary mass.

The medicine has been ineffective in a limited number of patients with intraocular cysticercosis, and the manufacturer and some clinicians state that praziquantel should not be used for this condition because of the risk of irreversible intraocular lesions caused by killing the cysts.

Dosage and administration

Administration

Praziquantel is taken by mouth. The tablets should not be chewed, but they can be halved or quartered to allow individualised doses. Patients should be told to swallow praziquantel tablets, halves and/or quarters straight away with enough liquid during meals, since keeping the tablets or tablet pieces in the mouth may cause gagging or vomiting because of the medicine's bitter taste.

Some clinicians state that regurgitation while taking the tablets may theoretically increase the risk of cysticercosis developing during treatment for T. solium infections.

Dosage

Trematode (fluke) infections: schistosomiasis

For schistosomiasis caused by all species of Schistosoma that infect humans, the usual dose of praziquantel recommended by the manufacturer in adults and children aged 4 years and over is 60 mg/kg given in 3 equally divided doses on the same day.

Some clinicians recommend lower doses (40 mg/kg given as a single dose or in 2 equally divided doses), which have been effective in some patients with schistosomiasis. Some clinicians recommend that adults or children with schistosomiasis caused by S. haematobium or S. mansoni receive praziquantel 40 mg/kg in 2 equally divided doses on the same day, and that those with infections caused by S. japonicum or S. mekongi receive 60 mg/kg in 3 equally divided doses on the same day.

Clonorchiasis and opisthorchiasis

For infections caused by Clonorchis sinensis or Opisthorchis viverrini, the usual dosage of praziquantel in adults and children is 75 mg/kg given in 3 equally divided doses on the same day. Lower doses (40-50 mg/kg given as a single dose) have been effective in some patients; however, these doses may be associated with lower cure rates.

Other trematode infections

For trematodiasis caused by Fasciolopsis buski, Heterophyes heterophyes, or Metagonimus yokogawai, the usual dosage of praziquantel in adults and children is 75 mg/kg given in 3 equally divided doses on the same day.

Nanophyetus salmincola

For trematode infections caused by Nanophyetus salmincola, the usual dosage of praziquantel in adults and children is 60 mg/kg given in 3 equally divided doses on the same day.

For trematodiasis caused by Fasciola hepatica, a dosage of 25 mg/kg 3 times daily for 5-8 days has been used in a limited number of adults and children, but treatment failures have occurred.

Paragonimus westermani

For trematode infections caused by Paragonimus westermani, the usual dosage in adults and children is 25 mg/kg 3 times daily for 2 days. For trematodiasis caused by P. uterobilateralis, a dosage of 25 mg/kg 3 times daily for 2 days has been effective.

Cestode (tapeworm) infections: adult (intestinal) stage

For cestodiasis caused by Diphyllobothrium latum, Dipylidium caninum, Taenia saginata, or T. solium, the usual dose of praziquantel in adults and children is 5-10 mg/kg given as a single dose. For cestodiasis caused by Hymenolepis nana, the usual dose in adults and children is 25 mg/kg given as a single dose.

Larval (tissue) stage

For cysticercosis caused by Cysticercus cellulosae, the usual dosage of praziquantel in adults and children is 50-100 mg/kg given in 3 divided doses daily for 30 days.

A praziquantel dosage of 50 mg/kg given in 3 equally divided doses daily for 14 or 15 days has usually been used to treat neurocysticercosis; this dosage has also been used for 21 days in a few patients.

Because of the risk of praziquantel-related nervous system side effects, most clinicians recommend that corticosteroids (for example, dexamethasone 6-24 mg daily, prednisone 30-60 mg daily) be given at the same time as praziquantel in patients with neurocysticercosis.

Although the possible benefit of additional courses of praziquantel treatment in adults with neurocysticercosis has not been established, some clinicians suggest that repeated courses may be useful in patients who show only partial resolution of cysts 3 months after a course or whose condition worsens.

Cautions

At recommended doses, praziquantel is generally well tolerated. Side effects are common, but they are usually temporary and mild to moderate, and they usually do not need treatment. Some side effects may be caused by the parasitic infection itself and/or by dead and dying parasites rather than by the medicine, and these effects may be more common and/or more severe in patients with a heavy worm burden.

Nervous system effects

Nervous system side effects occur frequently with praziquantel; however, most are mild and temporary. The most common are dizziness, headache and malaise. Other nervous system side effects include drowsiness and lassitude (fatigue). Giddiness has rarely been reported.

Nervous system side effects (CSF reaction syndrome), including headache, worsening of neurological signs and symptoms such as seizures, increased CSF protein concentrations and anticysticercal immunoglobulin G (IgG) levels, arachnoiditis, meningism, hyperthermia, and intracranial hypertension, occur in almost all patients during praziquantel treatment for neurocysticercosis and may rarely be life-threatening.

CSF reaction syndrome is thought to result from a strong inflammatory response to dead and dying larvae in the CNS and may be similar to the Jarisch-Herxheimer reaction seen during penicillin treatment for syphilis. The risk of serious reactions is probably related to the number, size and location of viable cysts in the CNS. Using corticosteroids at the same time as praziquantel for neurocysticercosis reportedly greatly reduces how often these nervous system side effects occur and how severe they are.

GI effects

Gastrointestinal (GI) side effects occur frequently. Abdominal pain or discomfort, with or without nausea, occurs in about 90% of patients receiving the medicine. Vomiting, epigastric pain, anorexia, an urge to defecate, and diarrhoea have also been reported.

GI reactions, mainly colicky, cramping abdominal pain, can occasionally be severe and may occur suddenly within 1 hour after taking the medicine. These reactions may be accompanied by fever, sweating and bloody stools.

Hepatic effects

Mild to moderate, temporary increases in serum aspartate aminotransferase (AST; formerly SGOT) and/or alanine aminotransferase (ALT; formerly SGPT) concentrations have occurred in about 3-27% of patients receiving praziquantel. However, there has been no evidence of serious medicine-induced hepatic effects, even in patients with schistosomal infection associated with severe hepatosplenic involvement.

Other side effects

Urticaria, rash (for example, maculopapular rash), pruritus, low back pain, myalgia or arthralgia, fever or a hot sensation, sweating, palpitations, and hypotension have been reported in some patients receiving praziquantel.

Small increases in eosinophil count have occurred in a few patients with schistosomiasis treated with the medicine. However, eosinophilia is also associated with schistosomiasis and may also result from a host immune response to antigen release during medicine-induced killing of the worms. Similarly, urticaria may result from an immune response to antigen release from the worms.

Although praziquantel has been shown in vitro to induce a positive inotropic effect on rat atria, this effect has not been reported to date in humans receiving the medicine, and the clinical importance of this finding has not been established.

Precautions and contraindications

Patients should be warned that praziquantel may affect their ability to do activities that require mental alertness or physical coordination, such as operating machinery or driving. The manufacturer recommends that patients do not do these activities on the day of treatment and the following day.

Some clinicians state that praziquantel should be used with caution in patients with a history of seizures. Praziquantel is contraindicated in patients who are hypersensitive to the medicine. The manufacturer and some clinicians also state that it is contraindicated in patients with intraocular cysticercosis. In addition, some clinicians recommend that praziquantel should not be used in patients with spinal cysticercosis.

Paediatric precautions

The safety of praziquantel in children younger than 4 years has not been established.

Mutagenicity and carcinogenicity

It is not known whether praziquantel is mutagenic or carcinogenic in humans. Although one laboratory reported that praziquantel was mutagenic in bacteria, these results have not been reproducible, and other studies have not shown the medicine to be mutagenic in bacteria or mammalian cells.

The medicine has been shown to act as a comutagen, increasing the mutagenicity of several mutagenic and/or carcinogenic chemicals in vitro in bacteria and animal cells. No evidence of carcinogenesis was seen in animals receiving oral praziquantel doses up to 250 mg/kg once weekly for 2 years.

Pregnancy, fertility and lactation

Reproduction studies in rats and rabbits using praziquantel doses up to 40 times the usual human dose have not shown evidence of harm to the fetus. An increase in the rate of spontaneous abortion occurred in rats after administration of praziquantel doses 3 times the usual human dose.

There are currently no adequate and controlled studies of praziquantel in pregnant women, and the medicine should be used during pregnancy only when clearly needed. It is not known whether praziquantel affects fertility in humans. Reproduction studies in rats and rabbits using praziquantel doses up to 40 times the usual human dose have not shown evidence of impaired fertility.

Since praziquantel passes into breast milk, women should temporarily stop breastfeeding on the day of praziquantel treatment and for 72 hours after the last dose.

Drug interactions

Oxamniquine: Although the clinical importance is unclear, limited evidence from one study in mice suggests that the antischistosomal activity of praziquantel and oxamniquine (not generally commercially available in Australia) may be synergistic against Schistosoma mansoni when the two medicines are given together.

Acute toxicity

Limited information is available about the acute toxicity of praziquantel.

The acute lethal dose of praziquantel in humans has not been established. Toxicology studies in animals have shown that the oral median lethal dose (LD50) of praziquantel is about 2.5 g/kg in mice, about 2.8 g/kg in rats, 1.05 g/kg in rabbits, and greater than 200 mg/kg in dogs. However, an actual acute oral lethal dose could not be established in dogs because of the emetic effect of the medicine in this species.

Although there has been no experience to date with acute praziquantel overdose in humans, the manufacturer states that a fast-acting laxative should be given after acute ingestion of an overdose.

Mechanism of action

Activity against trematodes

The exact way praziquantel works against trematodes (flukes), including its antischistosomal activity, has not been fully explained. Praziquantel appears to directly kill susceptible adult schistosomes in vivo. In addition, the medicine causes dead or dying worms to become dislodged from their usual sites in the mesenteric or pelvic (for example, vesical plexus) veins and move to the liver, where they are retained and later trigger host tissue reactions such as phagocytosis.

The dislodgement appears to result mainly from contraction and paralysis of the worm musculature and the resulting immobilisation of their suckers, which causes the worms to detach from the blood vessel wall and then be passively carried away by normal blood flow. The drug-induced contraction and subsequent paralysis in the contracted state appear to result from increased permeability of the cell membrane of susceptible worms to calcium, with a resulting influx of calcium ions.

After praziquantel is given, intense, localised vacuolisation and subsequent disintegration occur at distinct sites in the schistosomal integument. This vacuolisation and disintegration create surface defects and cause most schistosomes to lose their normal copulatory position, which substantially reduces oviposition (egg laying).

Limited evidence suggests that male S. mansoni worms may be more susceptible than females; however, evidence from animal studies indicates that all worms were dead 7 days after treatment. The number of worms affected and the degree of integumental injury appear to be dose related; in addition, the degree of injury increases over time after treatment.

Studies in animals with experimentally induced schistosomal infections indicate that praziquantel is active against all developmental stages of schistosomes, including miracidia and cercariae (the free-swimming larvae that emerge from the intermediate snail host).

Activity Against Cestodes

Although the exact mechanism of praziquantel's activity against cestodes (tapeworms) has not been determined, the drug generally does not kill susceptible adult cestodes in vivo, but causes the worms to be dislodged from their usual sites in the intestine. This dislodgement appears to result from drug-induced impairment of the function of the worms' suckers.

The effects of praziquantel against cestodes are concentration dependent in vitro. At low concentrations (1-10 ng/mL), the drug stimulates cestode motility and impairs the function of their suckers. At higher concentrations, contraction of the strobila (chain of proglottids) occurs; at very high concentrations (greater than 1000 ng/mL), instantaneous, irreversible contraction occurs.

Praziquantel also causes irreversible focal vacuolisation and subsequent disintegration at specific sites of the cestodal integument. These lesions are restricted to the growth zone of the neck region; the proglottids of the central and posterior portions of the strobila are not affected.

Spectrum

Praziquantel has a broad spectrum of anthelmintic activity. The drug is active against many trematodes, including schistosomes, and also against many cestodes.

Trematodes

Praziquantel is active against all Schistosoma species that are pathogenic to humans, including S. mansoni, S. haematobium, S. japonicum, S. mekongi, and S. intercalatum. In vitro, susceptible schistosomes are rapidly killed by praziquantel concentrations of 0.3 mcg/mL and above.

Praziquantel has also been shown to be active against other trematodes, including the liver flukes Clonorchis sinensis, Opisthorchis viverrini, and Fasciola hepatica; the lung flukes Paragonimus westermani, P. uterobilateralis, and P. kellicotti; and the intestinal flukes Metagonimus yokogawai, Nanophyetus salmincola, Fasciolopsis buski, and Heterophyes heterophyes.

Cestodes

Praziquantel has been shown to be active against adult, juvenile, and larval stages of certain cestodes that are pathogenic to humans, including Diphyllobothrium latum, Dipylidium caninum, Hymenolepis nana, Taenia saginata, T. solium, and Cysticercus cellulosae.

Pharmacokinetics

Absorption

Praziquantel is well absorbed after oral administration. Approximately 80% of an oral dose is absorbed from the gastrointestinal tract; however, because of extensive first-pass metabolism, only a small portion reaches the systemic circulation as unchanged praziquantel. Peak serum concentrations occur about 1-3 hours after usual oral doses. Following a single 50-mg/kg dose in healthy adults in one study, peak serum drug concentrations of about 1 mcg/mL occurred at 1-2 hours.

Distribution

Distribution of praziquantel into human body tissues and fluids has not been fully characterised. In studies in rats, concentrations of free (unbound) praziquantel in CSF were similar to those in serum. The concentration of the drug in CSF is reported to be 14-20% of the concurrent total (free plus protein-bound) plasma concentration. Praziquantel is distributed into milk at concentrations about 25% of maternal serum concentrations.

Elimination

Praziquantel has a serum half-life of about 0.8-1.5 hours in adults with normal renal and hepatic function; however, the serum half-life of its metabolites is about 4-5 hours. Although the exact metabolic fate of praziquantel has not been clearly established, the drug is rapidly and extensively metabolised, mainly in the liver through hydroxylation to monohydroxylated and polyhydroxylated metabolites. It is not known whether these metabolites have anthelmintic activity.

Praziquantel and its metabolites are excreted mainly in the urine. Following a single oral dose, approximately 70-80% of the dose is excreted in the urine within 24 hours, mainly as metabolites; less than 0.1% of an oral dose is excreted in the urine unchanged.

Chemistry and Stability

Chemistry

Praziquantel, a pyrazinoisoquinoline derivative, is a synthetic heterocyclic anthelmintic agent. The drug is structurally unrelated to other currently available anthelmintic agents. Praziquantel occurs as a white to nearly white, hygroscopic, crystalline powder with a bitter taste and is very slightly soluble in water and soluble in alcohol.

Stability

Praziquantel tablets should be stored in tightly closed containers at a temperature below 30°C.