Fungiviz I

Uses

For the treatment of fungal corneal ulcers/ keratitis.

Ivermectin is used for the treatment of the following infections:

Strongyloidiasis of the intestinal tract. Ivermectin is used for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis.

This indication is based on clinical studies of both comparative and open-label designs, in which 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin.

Onchocerciasis: Ivermectin is used for the treatment of onchocerciasis due to the nematode parasite Onchocerca volvulus.

This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C).

NOTE: Ivermectin has no activity against adult Onchocerca volvulus parasites. The adult parasites reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules (nodulectomy) may be considered in the management of patients with onchocerciasis, since this procedure will eliminate the microfilariae-producing adult parasites.

Fungiviz I is also used to associated treatment for these conditions: Candida intertrigo, Candida pneumonia, Candida urinary tract infection, Candidemia, Candidiasis, Coccidioidomycosis, Esophageal Candidiasis, Fungal peritonitis caused by Candida, Infections, Fungal, Meningitis, Cryptococcal, Oropharyngeal Candidiasis, Peritoneal candidiasis, Pneumonia cryptococcal, Pruritus, Skin Irritation, Systemic Candida Infections caused by Candida, Vaginal Candidiasis, Disseminated CandidiasisAcne Rosacea, Ascaris lumbricoides infection, Cutaneous larva migrans, Demodicidosis, Gnathostomiasis, Mansonella ozzardi infection, Mansonella streptocerca infection, Oesophagostomiasis, Onchocerciasis, Pediculosis Capitis, Scabies, Trichuriasis, Wuchereria bancroftii infection

How Fungiviz I works

Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme normally works to convert lanosterol to ergosterol, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane.

Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing.

Ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the parasite. Ivermectin also is believed to act as an agonist of the neurotransmitter gamma-aminobutyric acid (GABA), thereby disrupting GABA-mediated central nervous system (CNS) neurosynaptic transmission. Ivermectin may also impair normal intrauterine development of O. volvulus microfilariae and may inhibit their release from the uteri of gravid female worms.

Dosage

Fungiviz I dosage

Instill 1 drop to be instilled into the affected eye(s) 5 times daily.

Oral

Filariasis:

• Adult: Dosing regimen depends on the causative agent. Mansonella streptocerca 150 mcg/kg as a single dose; Mansonella ozzardi 200 mcg/kg as a single dose.
• Child: ≥15 kg: Dosing regimen depends on the causative agent. Mansonella streptocerca 150 mcg/kg as a single dose; Mansonella ozzardi 200 mcg/kg as a single dose.

Scabies:

• Adult: Sarcoptes scabiei 200 mcg/kg as a single dose, repeat dose in 2 wk.
• Child: ≥15 kg: Sarcoptes scabiei 200 mcg/kg as a single dose, repeat dose in 2 wk.

Onchocerciasis:

• Adult:150 mcg/kg as a single dose; retreatment may be given every 6-12 mth until adult worms die.
• Child: >5 yr and ≥15kg: 150 mcg/kg as a single dose every 6-12 mth until adult worms die.

Ascariasis:

• Adult: Ascaris lumbricoides 150-200 mcg/kg as a single dose.
• Child: ≥15 kg: Ascaris lumbricoides 150-200 mcg/kg as a single dose.

Strongyloidiasis:

• Adult: 200 mcg/kg as a single dose for 1-2 days.
• Child: >15 kg: 200 mcg/kg as a single dose for 1-2 days.

Gnathostomiasis:

• Adult: Gnathostoma spinigerum: 200 mcg/kg once daily for 2 days.
• Child: ≥15 kg: Gnathostoma spinigerum: 200 mcg/kg once daily for 2 days.

Should be taken on an empty stomach.

Side Effects

This drug is generally well tolerated. Eosinophillia has been reported in some patients.

Diarrhoea, nausea, vomiting, dizziness, pruritus, urticaria, rash, arthralgia, fever, myalgia, asthenia, postural hypotension, tachycardia, oedema, lymphadenopathy, sore throat, cough, headache, somnolence, transient eosinophilia, raised liver enzyme values.

Toxicity

Acute oral toxicity (LD50): 1271 mg/kg (rat)

Overdose information

Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination. In cases of overdose, employ supportive treatment. Gastric lavage may be necessary. Other modalities such as forced diuresis or hemodialysis may also be used.

A note on liver toxicity

The FDA label warns that this drug carries a risk of hepatotoxicity. Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole. This group of patients has an increased risk of fatality when using fluconazole. In patients with existing liver dysfunction, use caution during fluconazole therapy. Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver. Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. Fluconazole induced hepatotoxicity is usually reversible.

Carcinogenesis, mutagenesis, and impairment of fertility

Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated orally for 24 months at doses equivalent to approximately 2-7 time the recommended human dose). Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas. Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation. The significance of these findings for humans is unknown.

Use in pregnancy

There are no sufficient and well-controlled studies of fluconazole use in pregnant women. Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (27 Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy. Similar findings were observed in animal studies. If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly.

Use in nursing

Fluconazole is secreted in breastmilk at high concentrations. Exercise caution if this drug is used during nursing.

LD₅₀ = 29.5 mg/kg (Mouse, oral). LD₅₀ = 10 mg/kg (Rat, oral). Adverse effects include muscle or joint pain, dizziness, fever, headache, skin rash, fast heartbeat.

Precaution

Use of fluconazole may result in overgrowth of non-susceptible strains of candida other than Candida albicans

Concurrent Loa loa infection, impaired blood-brain barrier function due to infection.

Interaction

Fluconazole can alter pharmacokinetics of certain drugs undergoing hepatic metabolism.

Bioavailability may be increased by alcohol, levamisole.

Volume of Distribution

The apparent volume of distribution is said to be similar to the volume of distribution of total body water. One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39L, based on a body weight of 60kg.

Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat. Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections.[L6496] Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations. In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels. Therefore, fluconazole crosses the blood-brain barrier[L6496]. The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.

The volume of distribution is 3 to 3.5 L/kg and it does not cross the blood-brain barrier.

Elimination Route

The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (IV) and oral (PO) routes. In healthy volunteers, the bioavailability of orally administered fluconazole is measured to be above 90%. It is extensively absorbed in the gastrointestinal tract when an oral dose is taken. Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached.

Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours.

Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose. Steady-state concentrations are achieved within 5 to 10 days after oral doses of 50-400 mg administered once daily. Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day. Mean AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole.

A note on the capsule and powder form and malabsorption syndromes

The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose. The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency.

Moderately well absorbed. Improved absorption with high fat meal.

Half Life

The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration. The long plasma elimination half-life supports a single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.[L6496]. Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.

16 hours (also reported at 22-28 hours)

Clearance

This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg. One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h).

Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.

Elimination Route

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose measured in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.. A study of a 50mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine.

A note on renal failure

The pharmacokinetics of fluconazole are significantly affected by renal dysfunction. The dose of fluconazole may need to be reduced in patients with decreased renal function. A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.

Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine.

Pregnancy & Breastfeeding use

Use in pregnancy: Pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Fluconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Nursing mother should not be given as the drug is excreted in breast milk in concentration similar to plasma.

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

The drug is contraindicated in patients with hypersensitivity to azoles.

Hypersensitivity. Pregnancy and lactation. Children <15 kg body weight.

Storage Condition

Keep out of the reach of children. Store in a cool, dry place, away from heat and direct light. Do not use more than 4 weeks after opening the bottle

Store below 30°C.

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