Alinia(nitazoxanide) tablets - America[美国药品]

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Alinia(nitazoxanide) tablets

2015-12-28 06:56:59 来源: 作者: 【大中小】浏览:358次评论:0条

DESCRIPTION

Alinia Tablets and Alinia for Oral Suspension contain the active ingredient, nitazoxanide, a synthetic antiprotozoal agent for oral administration. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, nitazoxanide is 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide. The molecular formula is C12H9N3O5S and the molecular weight is 307.3. The structural formula is:

Alinia Tablets contain 500 mg of nitazoxanide and the following inactive ingredients: maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake.

Alinia for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of a homogeneous suspension with a pink color that contains 100 mg nitazoxanide per 5 mL and the following inactive ingredients: sodium benzoate, sucrose, xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, anhydrous citric acid, sodium citrate dihydrate, maltodextrin, modified food starch, triacetin, FD&C Red #40 and artificial strawberry flavoring.

CLINICAL PHARMACOLOGY

Absorption: Following oral administration of Alinia Tablets or Oral Suspension, maximum plasma concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are observed within 1-4 hours. The parent nitazoxanide is not detected in plasma. Pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide are shown in Tables 1 and 2 below.

Table 1. Mean (±SD) plasma pharmacokinetic parameter values following administration of a single dose of one 500 mg Alinia Tablet with food to subjects ≥12 years of age
* Tmax is given as a Mean (Range)
	Tizoxanide			Tizoxanide glucuronide
Age	Cmax (μg/mL)	*Tmax (hr)	AUCτ (μg•hr/mL)	Cmax (μg/mL)	*Tmax (hr)	AUCτ (μg•hr/mL)
12-17 years	9.1 (6.1)	4.0 (1-4)	39.5 (24.2)	7.3 (1.9)	4.0 (2-8)	46.5 (18.2)
≥18 years	10.6 (2.0)	3.0 (2-4)	41.9 (6.0)	10.5 (1.4)	4.5 (4-6)	63.0 (12.3)

Table 2. Mean (±SD) plasma pharmacokinetic parameter values following administration of a single dose of Alinia for Oral Suspension with food to subjects ≥1 year of age
* Tmax is given as a Mean (Range)
	Tizoxanide				Tizoxanide glucuronide
Age	Dose	Cmax (μg/mL)	*Tmax (hr)	AUCinf (μg•hr/mL)	Cmax (μg/mL)	*Tmax (hr)	AUCinf (μg•hr/mL)
1-3 years	100 mg	3.11 (2.0)	3.5 (2-4)	11.7 (4.46)	3.64 (1.16)	4.0 (3-4)	19.0 (5.03)
4-11 years	200 mg	3.00 (0.99)	2.0 (1-4)	13.5 (3.3)	2.84 (0.97)	4.0 (2-4)	16.9 (5.00)
≥18 years	500 mg	5.49 (2.06)	2.5 (1-5)	30.2 (12.3)	3.21 (1.05)	4.0 (2.5-6)	22.8 (6.49)

Alinia for Oral Suspension is not bioequivalent to Alinia Tablets. The relative bioavailability of the suspension compared to the tablet was 70%.

Effect of Food: When Alinia Tablets are administered with food, the AUCt of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the Cmax is increased by almost 50%.

When Alinia for Oral Suspension was administered with food, the AUCt of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the Cmax increased by ≤10%.

Alinia Tablets and for Oral Suspension were administered with food in clinical trials and hence they are recommended to be administered with food (see DOSAGE AND ADMINISTRATION).

Multiple dosing: Following oral administration of a single Alinia Tablet every 12 hours for 7 consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma.

Distribution: In plasma, more than 99% of tizoxanide is bound to proteins.

Metabolism: Following oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation. In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

Elimination: Tizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the feces and one-third in the urine.

Special Populations

Patients with Impaired Hepatic and/or Renal Function: The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function has not been studied.

Geriatric Patients: The pharmacokinetics of nitazoxanide in geriatric patients has not been studied.

Pediatric Patients: The pharmacokinetics of nitazoxanide following administration of Alinia Tablets in pediatric patients less than 12 years of age has not been studied. The pharmacokinetics of nitazoxanide following administration of Alinia for Oral Suspension in pediatric patients less than 1 year of age has not been studied.

MICROBIOLOGY

Mechanism of Action

The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.

Activity in vitro

Nitazoxanide and its metabolite, tizoxanide, are active in vitro in inhibiting the growth of (i) sporozoites and oocysts of Cryptosporidium parvum and (ii) trophozoites of Giardia lamblia.

Drug Resistance

A potential for development of resistance by Cryptosporidium parvum or Giardia lamblia to nitazoxanide has not been examined.

Susceptibility Tests:

For protozoa such as Cryptosporidium parvum and Giardia lamblia, standardized tests for use in clinical microbiology laboratories are not available.

INDICATIONS AND USAGE

Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:

Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.