Ultac Actions

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Actions of Ultac in details

H₂-receptor antagonist.

Pharmacology: Ultac, a histamine H₂-receptor antagonist and cimetidine, a H₂-antagonist changed the management of peptic ulcers and substantially reduced the need for surgery in more severe cases. However, there are many shortcomings of cimetidine therapy due to its nonspecific action. Ultac is a new potent H₂-antagonist having highly specific action and 5-10 times more potent as compared to cimetidine.

Ultac is a competitive inhibitor of histamine at histamine H₂-receptor sites, including receptors on the gastric cells. Ultac inhibits both day time and nocturnal basal gastric acid secretions as well as gastric secretion by food, histamine and pentagastrin.

In healthy subjects and duodenal ulcer patients Ultac did not significantly alter serum gastrin, pancreatic or mucus secretion. Pepsin secretion is not decreased but its output is reduced in proportion to the decrease in volume of gastric juice.

Serum prolactin secretion is not increased in recommended doses. Ultac does not have anti-adrenergic effects in animals or humans and studies to date suggest it does not affect serum gonadotropins, TSH, GH, count, motility or morphology of sperms and hepatic metabolism of drugs.

Pharmacokinetics: Ultac is well-absorbed after oral administration and the peak plasma concentrations are achieved within 1-2 hrs.

Absorption is not significantly impaired by the administration of food or antacids. After a 150 mg oral dose, mean peak plasma concentration are about 400 mg/mL. Reported bioavailability after single doses has varied between 40-80% (average 50%). Ultac undergoes significant first-pass metabolism after oral administration. The elimination t_½ is about 2.5-3 hrs. Ultac is absorbed very rapidly after IM injection within 15 min or less following a 50 mg IM dose. Absorption from IM sites is virtually complete with a bioavailability of 90-100% compared with IV administration. The principal route of excretion of Ultac (tablet and injection) is urine. The N-oxide being the principal metabolite (4%). Other metabolites are the S-oxide (1%) and desmethyl Ultac (1%). The remainder of the administered dose is found in the stool. The serum protein-binding of Ultac averages 15%.

Following oral, IM, IV injections serum concentrations of Ultac are estimated to be 36-94 mg/mL which is necessary to inhibit 50% of stimulated gastric acid secretions.

How should I take Ultac?

Take Ultac exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Your doctor may recommend an antacid to help relieve pain. Carefully follow your doctor's directions about the type of antacid to use, and when to use it.

Do not crush, chew, or break the Ultac effervescent tablet, and do not allow it to dissolve on your tongue. The 25-milligram effervescent tablet must be dissolved in at least 1 teaspoon of water before swallowing. The150-milligram effervescent tablet should be dissolved in 6 to 8 ounces of water.

Allow the Ultac effervescent tablet to dissolve completely in the water, and then drink the entire mixture. If you are giving this medicine to a child, you may draw the liquid mixture into a medicine dropper and empty the dropper into the child's mouth.

Ultac granules should be mixed with 6 to 8 ounces of water before drinking.

Measure Ultac liquid with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

It may take up to 8 weeks before your ulcer heals. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 6 weeks of treatment.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using Ultac.

Store Ultac at room temperature away from moisture, heat, and light.

Ultac administration

Injection may be administered IM or IV:

IM: Injection is administered undiluted

IV: Must be diluted; may be administered intermittent bolus or intermittent IV infusion

Intermittent bolus: Manufacturer recommends a maximum rate of administration of 10 mg/minute (infuse over at least 5 minutes); however, in adults may also be administered at a maximum rate of 25 mg/minute (or over 2 minutes) if necessary (Coursin 1988; Goelzer 1988; Smith 1987).

Intermittent IV infusion: Administer over a maximum rate of 2.5 to 3.5 mg/minute (infuse over at least 15 to 20 minutes)

Ultac pharmacology

Ultac Tablets, USP are a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. Ultac Tablets, USP ds not lower serum Ca++ in hypercalcemic states. Ultac Tablets, USP are not an anticholinergic agent.

Pharmacokinetics: Absorption: Ultac Tablets, USP are 50% absorbed after oral administration, compared to an intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours after a 150-mg dose. Absorption is not significantly impaired by the administration of food or antacids. Propantheline slightly delays and increases peak blood levels of Ultac, probably by delaying gastric emptying and transit time. In one study, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of Ultac Tablets, USP.

Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages 15%.

Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl Ultac (1%). The remainder of the administered dose is found in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in Ultac half-life, distribution, clearance, and bioavailability.

Excretion: The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours. Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 mL/min) administered 50 mg of Ultac intravenously had an average plasma half-life of 4.8 hours, a Ultac clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In general, these parameters appear to be altered in proportion to creatinine clearance.

Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak levels average 526 ng/mL following a 150-mg twice daily dose and occur in about 3 hours.

Pediatrics: There are no significant differences in the pharmacokinetic parameter values for Ultac in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight. The average bioavailability of Ultac given orally to pediatric patients is 48% which is comparable to the bioavailability of Ultac in the adult population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those observed with intravenous Ultac use in pediatric patients. Estimates of Cmax and Tmax are displayed in Table 1.

Table 1. Ultac Pharmacokinetics in Pediatric Patients Following Oral Dosing
Population (age)	n	Dosage Form (dose)	Cmax (ng/mL	Tmax (hours)
Gastric or duodenal ulcer (3.5 to 16 years)	12	Tablets| (1 to 2 mg/kg)	54 to 492	2.0
Otherwise healthy requiring Ultac (0.7 to 14 years, Single dose)	10	Syrup (2 mg/kg)	244	1.61
Otherwise healthy requiring Ultac (0.7 to 14 years, Multiple dose)	10	Syrup (2 mg/kg)	320	1.66

Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed in this population.

Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of Ultac are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition.

Antisecretory Activity: 1. Effects on Acid Secretion: Ultac Tablets, USP inhibit both daytime and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food, betazole, and pentagastrin, as shown in Table 2.

Table 2. Effect of Oral Ultac Tablets, USP on Gastric Acid Secretion
	Time After Dose, hours	% Inhibition of Gastric Acid Output by Dose, mg
		75 to 80	100	150	200
Basal	Up to 4		99	95
Nocturnal	Up to 13	95	96	92
Betazole	Up to 3		97	99
Pentagastin	Up to 5	58	72	72	80
Meal	Up to 3		73	79	95

It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to inhibition by Ultac Tablets, USP, responding almost completely to doses of 100 mg or less, while pentagastrin- and food-stimulated secretions are more difficult to suppress.

2. Effects on Other Gastrointestinal Secretions:

Pepsin:

Oral Ultac Tablets, USP do not affect pepsin secretion. Total pepsin output is reduced in proportion to the decrease in volume of gastric juice.

Intrinsic Factor:

Oral Ultac Tablets, USP have no significant effect on pentagastrin-stimulated intrinsic factor secretion.

Serum Gastrin: Ultac Tablets, USP have little or no effect on fasting or postprandial serum gastrin.

Other Pharmacologic Actions:

1.Gastric bacterial flora-increase in nitrate-reducing organisms, significance not known.

2.Prolactin levels-no effect in recommended oral or intravenous (IV) dosage, but small, transient, dose-related increases in serum prolactin have been reported after IV bolus injections of 100 mg or more.

3.Other pituitary hormones-no effect on serum gonadotropins, TSH, or GH. Possible impairment of vasopressin release.

4.No change in cortisol, aldosterone, androgen, or estrogen levels.

5.No antiandrogenic action.

6.No effect on count, motility, or morphology of sperm.

Pediatrics:

Oral doses of 6 to 10 mg/kg/day in two or three divided doses maintain gastric pH>4 throughout most of the dosing interval.

Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with Ultac Tablets, USP as shown in Table 3

Table 3. Duodenal Ulcer Patient Healing Rates
	Ultac Tablets, USP *		Placebo*
	Number Entered	Healed / Evaluable	Number Entered	Healed / Evaluable
Outpatients	195	69/182 (38%) †	188	31-164 (19%)
Week 2
Week 4		137/187 (73%) †		76/168 (45%)

*All patients were permitted antacids as needed for relief of pain.

†P<0.0001.

In these studies, patients treated with Ultac Tablets, USP reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients.

Table 4. Mean Daily Doses of Antacid
	Ulcer Healed	Ulcer Not Healed
Ultac	0.06	0.71
Placebo	0.71	1.43

Foreign studies have shown that patients heal equally well with 150 mg twice daily and 300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice daily as compared to 300 mg at bedtime (92% versus 87%, respectively).

Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates.

Maintenance Therapy in Duodenal Ulcer: Ultac has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with Ultac Tablets, USP (150 mg at bedtime) than in patients treated with placebo over a 12-month period.

Table 5. Duodenal Ulcer Prevalence
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter Trial	Drug	Duodenal Ulcer Prevalence			No. Of Patients
		0 to 4 Months	0 to 8 Months	0 to 12 Months
USA	RAN	20%*	24%*	35%*	138
	PLC	44%	54%	59%	139
Foreign	RAN	12%*	21%*	28%*	174
	PLC	56%	64%	68%	165

% = Life table estimate.

* = P<0.05 (Ultac Tablets, USP versus comparator).

RAN = Ultac (Ultac Tablets, USP)

PLC = placebo.

As with other H2-antogonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both.

Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with Ultac Tablets, USP as shown in Table 6.

Table 6. Gastric Ulcer Patient Healing Rates
	Ultac Tablets, USP *		Placebo*
	Number Entered	Healed / Evaluable	Number Entered	Healed / Evaluable
Outpatients	92	16/83 (19%) †	94	10/83 (12%)
Week 2
Week 6		50/73 (68%) †		35/69 (51%)

*All patients were permitted antacids as needed for relief of pain.

†P = 0.009.

In this multicenter trial, significantly more patients treated with Ultac Tablets, USP became pain free during therapy.

Maintenance of Healing of Gastric Ulcers: In two multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, Ultac Tablets, USP 150 mg at bedtime was significantly more effective than placebo in maintaining healing of gastric ulcers.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):

Ultac Tablets, USP inhibit gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative, "short-gut" syndrome, idiopathic). Use of Ultac Tablets, USP was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.

Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, Ultac Tablets, USP 150 mg twice daily was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ultac-treated patients consumed significantly less antacid than did placebo-treated patients.

The US trial indicated that Ultac Tablets, USP 150 mg twice daily significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods.

In two additional US multicenter, double-blind, placebo-controlled, 2-week trials, Ultac Tablets, USP 150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn.

Erosive Esophagitis: In two multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, Ultac Tablets, USP 150 mg 4 times daily was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn.

The erosive esophagitis healing rates were as follows:

Table 7. Erosive Esophagitis Patient Healing Rates
	Healed / Evaluable
	Placebo* n=229	Ultac Tablets, USP 150 mg 4 times daily* n=215
Week 4	43/198 (22%)	96/206 (47%) †
Week 8	63/176 (36%)	142/200 (71%) †
Week 12	92/159 (58%)	162/192 (84%) †

*All patients were permitted antacids as needed for relief of pain.

†P<0.001 versus placebo.

No additional benefit in healing of esophagitis or in relief of heartburn was seen with a Ultac dose of 300 mg 4 times daily.

Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, Ultac Tablets, USP 150 mg twice daily was significantly more effective than placebo in maintaining healing of erosive esophagitis.

References

1. NCIt. "Ranitidine: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).

Reviews

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Information checked by Dr. Sachin Kumar, MD Pharmacology