Clindamycin Foam

Generic Name: clindamycin phosphate

Dosage Form: aerosol, foam
CLINDAMYCIN PHOSPHATE FOAM, 1%

Rx Only

FOR TOPICAL USE ONLY.

NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.

Clindamycin Foam Description

Clindamycin Phosphate Foam, 1% contains clindamycin phosphate, USP, a topical antibiotic for topical dermatologic use. Clindamycin phosphate is a water-soluble ester of the semi-synthetic antibiotic produced by a 7 (S)-chloro-substitution of the 7 (R)-hydroxyl group of the parent antibiotic, lincomycin.

The chemical name for clindamycin phosphate is methyl 7-chloro-6, 7, 8 - trideoxy - 6 - (1 - methyl - trans - 4 - propyl - L - 2 - pyrrolidinecarboxamido) - 1 - thio - L - threo - α - D - galacto - octopyranoside 2-(dihydrogen phosphate), with the empirical formula C18H34CIN2O8PS, a molecular weight of 504.97. The following is the chemical structure:

Clindamycin Chemical Structure Image

Clindamycin Phosphate Foam, 1% contains clindamycin phosphate, USP, at a concentration equivalent to 10 mg clindamycin per gram in a thermolabile hydroethanolic foam vehicle consisting of cetyl alcohol, ethanol (58%), polysorbate 60, propylene glycol, purified water, and stearyl alcohol pressurized with a hydrocarbon (propane/butane) propellant.

Clindamycin Foam - Clinical Pharmacology

Pharmacokinetics

In an open label, parallel group study in 24 patients with acne vulgaris, 12 patients (3 male and 9 female) applied 4 grams of clindamycin phosphate foam, 1%, once-daily for five days, and 12 patients (7 male and 5 female) applied 4 grams of clindamycin phosphate topical gel, 1%, once daily for five days. On Day 5, the mean Cmax and AUC(0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for clindamycin phosphate topical gel.

Following multiple applications of clindamycin phosphate foam, 1% less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

Microbiology

The clindamycin component has been shown to have in vitro activity against Propionibacterium acnes, an organism which is associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product. Cross-resistance between clindamycin and erythromycin has been demonstrated.

Clinical Studies

In one multicenter, randomized, double-blind, vehicle-controlled clinical trial patients with mild to moderate acne vulgaris used clindamycin phosphate foam, 1% or the vehicle foam once daily for twelve weeks. Treatment response, defined as the proportion of patients clear or almost clear, based on the Investigator Static Global Assessment (ISGA), and the mean percent reductions in lesion counts at the end of treatment in this study are shown in the following table:

Indications and Usage for Clindamycin Foam

Clindamycin Phosphate Foam, 1% is indicated for topical application in the treatment of acne vulgaris. In view of the potential for diarrhea, bloody diarrhea and pseudomembranous colitis, the physician should consider whether other agents are more appropriate. (See CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.)

Contraindications

Clindamycin Phosphate Foam, 1% is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis.

Warnings

Orally and parenterally administered clindamycin has been associated with severe colitis, which may result in patient death. Use of the topical formulation of clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.

Studies indicate a toxin(s) produced by Clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Endoscopic examination may reveal pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of severe diarrhea. Antiperistaltic agents, such as opiates and diphenoxylate with atropine, may prolong and/or worsen the condition.

Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Avoid contact of clindamycin phosphate foam with eyes. If contact occurs, rinse eyes thoroughly with water.

Precautions

General

Clindamycin Phosphate Foam, 1% should be prescribed with caution in atopic individuals.

Drug Interactions

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.

Carinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of a 1% clindamycin phosphate gel similar to clindamycin phosphate foam was evaluated by daily application to mice for two years. The daily doses used in this study were approximately 3 to 15 times higher than the human dose of clindamycin phosphate from 5 milliliters of clindamycin phosphate foam, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals.

A 1% clindamycin phosphate gel similar to clinamycin phosphate foam caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight.

Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility.

Pregnancy

Teratogenic effects

Pregnancy Category B

Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate hydrochloride. These studies revealed no evidence of fetal harm. The highest dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin phosphate dose of 432 mg/kg. For a rat, this dose is 84 fold higher, and for a mouse 42 fold higher, than the anticipated human dose of clindamycin phosphate from clindamycin phosphate based on a mg/m2 comparison. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether clinamycin is excreted in human milk following use of Clindamycin Phosphate Foam, 1%. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied.

Geriatric Use

The clinical study with clindamycin phosphate foam did not include sufficient numbers of patients aged 65 and over to determine if they respond differently than younger patients.

Adverse Reactions

The incidence of adverse events occurring in ≥ 1% of the patients in clinical studies comparing clindamycin phosphate foam and its vehicle is presented below:

In a contact sensitization study, none of the 203 subjects developed evidence of allergic contact sensitization to clindamycin phosphate foam, 1%.

Orally and parenterally administered clindamycin has been associated with severe colitis, which may end fatally.

Cases of diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely with topical clindamycin (see WARNINGS). Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, have also been reported in association with the use of topical formulations of clindamycin.

Overdosage

Topically applied Clindamycin Phosphate Foam, 1% may be absorbed in sufficient amounts to produce systemic effects (see WARNINGS).

Clindamycin Foam Dosage and Administration

Apply Clindamycin Phosphate Foam, 1% once daily to affected areas after the skin is washed with mild soap and allowed to fully dry. Use enough to cover the entire affected area.

How is Clindamycin Foam Supplied

Clindamycin Phosphate Foam, 1%, containing clindamycin phosphate equivalent to 10 mg clindamycin per gram, is available as follows:

100 gram can (NDC 45802-660-33)

50 gram can (NDC 45802-660-32)

STORAGE AND HANDLING

Store at 20 – 25°C (68 – 77°F) [see USP Controlled Room Temperature].

FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING AND IMMEDIATELY FOLLOWING APPLICATION.

Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperature above 120°F (49°C).

Keep out of reach of children.

MADE IN ISRAEL

MANUFACTURED BY

PERRIGO

YERUHAM 80500, ISRAEL

DISTRIBUTED BY

PERRIGO®

ALLEGAN, MI 49010

Rev. 05/09

: 4T500 RC J1

Principal Display Panel - 50 g Carton

Clindamycin Phosphate Foam, 1%

Rx Only

Clindamycin Phosphate Foam, 1% 50 g Carton

Principal Display Panel - 50 g Label

Clindamycin Phosphate Foam, 1%

Rx Only

Clindamycin Phosphate Foam, 1% 50 g Label

CLINDAMYCIN PHOSPHATE  clindamycin phosphate  aerosol, foam

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 45802-660 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLINDAMYCIN PHOSPHATE (CLINDAMYCIN) CLINDAMYCIN 10 mg  in 1 g

Inactive Ingredients Ingredient Name Strength ETHANOL   POLYSORBATE 60   PROPYLENE GLYCOL   WATER   STEARYL ALCOHOL   CETYL ALCOHOL

Product Characteristics Color WHITE Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 45802-660-32 1 CAN In 1 CARTON contains a CAN 1 50 g In 1 CAN This package is contained within the CARTON (45802-660-32) 2 45802-660-33 1 CAN In 1 CARTON contains a CAN 2 100 g In 1 CAN This package is contained within the CARTON (45802-660-33)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA090785	03/31/2010

Labeler - Perrigo New York Inc (078846912)

Revised: 04/2011Perrigo New York Inc

More Clindamycin Foam resources

• Clindamycin Foam Use in Pregnancy & Breastfeeding
• Clindamycin Foam Drug Interactions
• Clindamycin Foam Support Group
• 20 Reviews for Clindamycin - Add your own review/rating

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International Drug Name Search

Nizatidine

Nizatidine Capsules USP

Rx only

Nizatidine Description

Nizatidine USP is a histamine H2-receptor antagonist. Chemically, it is N - [2 - [[[2 - [(dimethylamino)methyl] - 4 - thiazolyl]methyl]thio]ethyl] - N’ - methyl - 2 - nitro - 1,1 - ethenediamine.

The structural formula is as follows:

Nizatidine has the empirical formula C12H21N5O2S2 representing a molecular weight of 331.46. It is an off-white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor.

Each capsule for oral administration contains Nizatidine 150 mg (0.45 mmol) or 300 mg (0.91 mmol), pregelatinized starch, povidone, corn starch, talc, croscarmellose sodium, dimethicone, gelatin, titanium dioxide, pharmaceutical glaze (modified), synthetic black iron oxide, propylene glycol, FD&C blue No. 2 aluminum lake, FD&C red No. 40 aluminum lake, FD&C blue No. 1 aluminum lake, and D&C yellow No. 10 aluminum lake. The 150 mg capsule also contains yellow iron oxide, and the 300 mg capsule also contains D&C red No. 28, FD&C blue No. 1, and FD&C yellow No. 6.

Nizatidine - Clinical Pharmacology

Nizatidine is a competitive, reversible inhibitor of histamine at the histamine H2-receptors, particularly those in the gastric parietal cells.

Antisecretory Activity

Effects on Acid Secretion

 Nizatidine significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Nizatidine also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).

Table 1: Effect of Oral Nizatidine on Gastric Acid Secretion

	Time After Dose (h)	% Inhibition of Gastric Acid Output by Dose (mg)
		20 - 50	75	100	150	300
Nocturnal	Up to 10	57	---	73	---	90
Betazole	Up to 3	---	93	---	100	99
Pentagastrin	Up to 6	---	25	---	64	67
Meal	Up to 4	41	64	---	98	97
Caffeine	Up to 3	---	73	---	85	96

Effects on Other Gastrointestinal Secretions

 Pepsin

 Oral administration of 75 mg to 300 mg of Nizatidine did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions.

Intrinsic Factor

Oral administration of 75 mg to 300 mg of Nizatidine increased betazole-stimulated secretion of intrinsic factor.

Serum Gastrin

Nizatidine had no effect on basal serum gastrin concentration. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of Nizatidine.

Other Pharmacologic Actions

 Hormones

Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.

Nizatidine had no demonstrable antiandrogenic action.

Pharmacokinetics

 The absolute oral bioavailability of Nizatidine exceeds 70%. Peak plasma concentrations (700 mcg/L to 1800 mcg/L for a 150 mg dose and 1400 mcg/L to 3600 mcg/L for a 300 mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1000 mcg/L is equivalent to 3 μmol/L; a dose of 300 mg is equivalent to 905 μmoles. Plasma concentrations 12 hours after administration are less than 10 mcg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 L/h to 60 L/h, and the volume of distribution is 0.8 L/kg to 1.5 L/kg. Because of the short half-life and rapid clearance of Nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Nizatidine exhibits dose proportionality over the recommended dose range.

The oral bioavailability of Nizatidine is unaffected by concomitant ingestion of the propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of Nizatidine by about 10%. With food, the AUC and Cmax increase by approximately 10%.

In humans, less than 7% of an oral dose is metabolized as N2-monodesmethylNizatidine, an H2-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose).

More than 90% of an oral dose of Nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces.

Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of Nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 L/h to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of Nizatidine should be reduced in proportion to the severity of dysfunction (see DOSAGE AND ADMINISTRATION).

Approximately 35% of Nizatidine is bound to plasma protein, mainly to α1-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of Nizatidine in vitro.

Clinical Trials

1. Active Duodenal Ulcer

 In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of Nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.

Table 2: Healing Response of Ulcers to Nizatidine

* P<0.01 as compared with placebo. † P<0.05 as compared with placebo.
	Nizatidine				Placebo
	300 mg h.s.		150 mg b.i.d.
	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable	Number Entered	Healed/ Evaluable
STUDY 1
Week 2			276	93/265 (35%)*	279	55/260 (21%)
Week 4				198/259 (76%)*		95/243 (39%)
STUDY 2
Week 2	108	24/103 (23%)*	106	27/101 (27%)*	101	9/93 (10%)
Week 4		65/97 (67%)*		66/97 (68%)*		24/84 (29%)
STUDY 3
Week 2	92	22/90 (24%)†			98	13/92 (14%)
Week 4		52/85 (61%)*				29/88 (33%)
Week 8		68/83 (82%)*				39/79 (49%)

2. Maintenance of Healed Duodenal Ulcer

 Treatment with a reduced dose of Nizatidine has been shown to be effective as maintenance therapy following healing of active duodenal ulcers. In multi-center, double-blind, placebo-controlled studies conducted in the United States, 150 mg of Nizatidine taken at bedtime resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated for up to 1 year (Table 3).

Table 3: Percentage of Ulcers Recurring by 3, 6, and 12 Months in Double-Blind Studies Conducted in the United States

* P<0.001 as compared with placebo.
Month	Nizatidine, 150 mg h.s.	Placebo
3	13% (28/208)*	40% (82/204)
6	24% (45/188)*	57% (106/187)
12	34% (57/166)*	64% (112/175)

3. Gastroesophageal Reflux Disease (GERD)

 In 2 multi-center, double-blind, placebo-controlled clinical trials performed in the United States and Canada, Nizatidine was more effective than placebo in improving endoscopically diagnosed esophagitis and in healing erosive and ulcerative esophagitis.

In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of Nizatidine given to 88 patients compared with placebo in 98 patients in Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05). Of 99 patients on Nizatidine and 94 patients on placebo, Study 2 at the same dosage yielded similar results at 6 weeks (21% vs 11%, P< 0.05) and at 12 weeks (29% vs 13%, P<0.01).

In addition, relief of associated heartburn was greater in patients treated with Nizatidine. Patients treated with Nizatidine consumed fewer antacids than did patients treated with placebo.

4. Active Benign Gastric Ulcer

 In a multicenter, double-blind, placebo-controlled study conducted in the United States and Canada, endoscopically diagnosed benign gastric ulcers healed significantly more rapidly following administration of Nizatidine than of placebo (Table 4).

Table 4

* P-values are one-sided, obtained by Chi-square test, and not adjusted for multiple comparisons.
Week	Treatment	Healing Rate	vs. Placebo p-value*
4	Nizatidine 300 mg h.s.	52/153 (34%)	0.342
	Nizatidine 150 mg b.i.d.	65/151 (43%)	0.022
	Placebo	48/151 (32%)
8	Nizatidine 300 mg h.s.	99/153 (65%)	0.011
	Nizatidine 150 mg b.i.d.	105/151 (70%)	<0.001
	Placebo	78/151 (52%)

In a multicenter, double-blind, comparator-controlled study in Europe, healing rates for patients receiving Nizatidine (300 mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients receiving a comparator drug, and statistically superior to historical placebo control rates.

Indications and Usage for Nizatidine

Nizatidine capsules USP are indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.

Nizatidine capsules USP are indicated for maintenance therapy for duodenal ulcer patients, at a reduced dosage of 150 mg h.s. after healing of an active duodenal ulcer. The consequences of continuous therapy with Nizatidine capsules USP for longer than 1 year are not known.

Nizatidine capsules USP are indicated for up to 12 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis, and associated heartburn due to GERD.

Nizatidine capsules USP are indicated for up to 8 weeks for the treatment of active benign gastric ulcer. Before initiating therapy, care should be taken to exclude the possibility of malignant gastric ulceration.

Contraindications

Nizatidine is contraindicated in patients with known hypersensitivity to the drug. Because cross- sensitivity in this class of compounds has been observed, H2-receptor antagonists, including Nizatidine, should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.

Precautions

General

1. Symptomatic response to Nizatidine therapy does not preclude the presence of gastric malignancy.

2. Because Nizatidine is excreted primarily by the kidney, dosage should be reduced in patients with moderate to severe renal insufficiency (see DOSAGE AND ADMINISTRATION).

3. Pharmacokinetic studies in patients with hepatorenal syndrome have not been done. Part of the dose of Nizatidine is metabolized in the liver. In patients with normal renal function and uncomplicated hepatic dysfunction, the disposition of Nizatidine is similar to that in normal subjects.

Laboratory Tests

False-positive tests for urobilinogen with Multistix® may occur during therapy with Nizatidine.

Drug Interactions

No interactions have been observed between Nizatidine and theophylline, chlordiazepoxide, lorazepam, lidocaine, phenytoin, and warfarin. Nizatidine does not inhibit the cytochrome P-450-linked drug-metabolizing enzyme system; therefore, drug interactions mediated by inhibition of hepatic metabolism are not expected to occur. In patients given very high doses (3900 mg) of aspirin daily, increases in serum salicylate levels were seen when Nizatidine, 150 mg b.i.d., was administered concurrently.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year oral carcinogenicity study in rats with doses as high as 500 mg/kg/day (about 80 times the recommended daily therapeutic dose) showed no evidence of a carcinogenic effect. There was a dose-related increase in the density of enterochromaffin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study in mice, there was no evidence of a carcinogenic effect in male mice; although hyperplastic nodules of the liver were increased in the high-dose males as compared with placebo. Female mice given the high dose of Nizatidine (2000 mg/kg/day, about 330 times the human dose) showed marginally statistically significant increases in hepatic carcinoma and hepatic nodular hyperplasia with no numerical increase seen in any of the other dose groups. The rate of hepatic carcinoma in the high-dose animals was within the historical control limits seen for the strain of mice used. The female mice were given a dose larger than the maximum tolerated dose, as indicated by excessive (30%) weight decrement as compared with concurrent controls and evidence of mild liver injury (transaminase elevations). The occurrence of a marginal finding at high dose only in animals given an excessive and somewhat hepatotoxic dose, with no evidence of a carcinogenic effect in rats, male mice, and female mice (given up to 360 mg/kg/day, about 60 times the human dose), and a negative mutagenicity battery are not considered evidence of a carcinogenic potential for Nizatidine.

Nizatidine was not mutagenic in a battery of tests performed to evaluate its potential genetic toxicity, including bacterial mutation tests, unscheduled DNA synthesis, sister chromatid exchange, mouse lymphoma assay, chromosome aberration tests, and a micronucleus test.

In a 2-generation, perinatal and postnatal fertility study in rats, doses of Nizatidine up to 650 mg/kg/day produced no adverse effects on the reproductive performance of parental animals or their progeny.

Pregnancy

Teratogenic Effects

Pregnancy Category B

 Oral reproduction studies in pregnant rats at doses up to 1500 mg/kg/day (9000 mg/m2/day, 40.5 times the recommended human dose based on body surface area) and in pregnant rabbits at doses up to 275 mg/kg/day (3245 mg/m2/day, 14.6 times the recommended human dose based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus due to Nizatidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies conducted in lactating women have shown that 0.1% of the administered oral dose of Nizatidine is secreted in human milk in proportion to plasma concentrations. Because of the growth depression in pups reared by lactating rats treated with Nizatidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the 955 patients in clinical studies who were treated with Nizatidine, 337 (35.3%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

Worldwide, controlled clinical trials of Nizatidine included over 6,000 patients given Nizatidine in studies of varying durations. Placebo-controlled trials in the United States and Canada included over 2,600 patients given Nizatidine and over 1,700 given placebo. Among the adverse events in these placebo-controlled trials, anemia (0.2% vs 0%) and urticaria (0.5% vs 0.1%) were significantly more common in the Nizatidine group.

Incidence in Placebo-Controlled Clinical Trials in the United States and Canada

Table 5 lists adverse events that occurred at a frequency of 1% or more among Nizatidine-treated patients who participated in placebo-controlled trials. The cited figures provide some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Table 5: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled Clinical Trials in the United States and Canada

* Events reported by at least 1% of Nizatidine-treated patients are included.
	Percentage of Patients Reporting Event
Body System/ Adverse Event*	Nizatidine (N=2,694)	Placebo (N=1,729)
Body as a Whole
Headache	16.6	15.6
Abdominal Pain	7.5	12.5
Pain	4.2	3.8
Asthenia	3.1	2.9
Back Pain	2.4	2.6
Chest Pain	2.3	2.1
Infection	1.7	1.1
Fever	1.6	2.3
Surgical Procedure	1.4	1.5
Injury, Accident	1.2	0.9
Digestive
Diarrhea	7.2	6.9
Nausea	5.4	7.4
Flatulence	4.9	5.4
Vomiting	3.6	5.6
Dyspepsia	3.6	4.4
Constipation	2.5	3.8
Dry Mouth	1.4	1.3
Nausea and Vomiting	1.2	1.9
Anorexia	1.2	1.6
Gastrointestinal Disorder	1.1	1.2
Tooth Disorder	1.0	0.8
Musculoskeletal
Myalgia	1.7	1.5
Nervous
Dizziness	4.6	3.8
Insomnia	2.7	3.4
Abnormal Dreams	1.9	1.9
Somnolence	1.9	1.6
Anxiety	1.6	1.4
Nervousness	1.1	0.8
Respiratory
Rhinitis	9.8	9.6
Pharyngitis	3.3	3.1
Sinusitis	2.4	2.1
Cough, Increased	2.0	2.0
Skin and Appendages
Rash	1.9	2.1
Pruritus	1.7	1.3
Special Senses
Amblyopia	1.0	0.9

A variety of less common events were also reported; it was not possible to determine whether these were caused by Nizatidine.

Hepatic: Hepatocellular injury, evidenced by elevated liver enzyme tests (SGOT [AST], SGPT [ALT], or alkaline phosphatase), occurred in some patients and was possibly or probably related to Nizatidine. In some cases, there was marked elevation of SGOT, SGPT enzymes (greater than 500 IU/L) and, in a single instance, SGPT was greater than 2000 IU/L. The overall rate of occurrences of elevated liver enzymes and elevations to 3 times the upper limit of normal, however, did not significantly differ from the rate of liver enzyme abnormalities in placebo-treated patients. All abnormalities were reversible after discontinuation of Nizatidine. Since market introduction, hepatitis and jaundice have been reported. Rare cases of cholestatic or mixed hepatocellular and cholestatic injury with jaundice have been reported with reversal of the abnormalities after discontinuation of Nizatidine.

Cardiovascular: In clinical pharmacology studies, short episodes of asymptomatic ventricular tachycardia occurred in 2 individuals administered Nizatidine and in 3 untreated subjects.

CNS: Rare cases of reversible mental confusion have been reported.

Endocrine: Clinical pharmacology studies and controlled clinical trials showed no evidence of antiandrogenic activity due to Nizatidine. Impotence and decreased libido were reported with similar frequency by patients who received Nizatidine and by those given placebo. Rare reports of gynecomastia occurred.

Hematologic: Anemia was reported significantly more frequently in Nizatidine- than in placebo-treated patients. Fatal thrombocytopenia was reported in a patient who was treated with Nizatidine and another H2-receptor antagonist. On previous occasions, this patient had experienced thrombocytopenia while taking other drugs. Rare cases of thrombocytopenic purpura have been reported.

Integumental: Sweating and urticaria were reported significantly more frequently in Nizatidine- than in placebo-treated patients. Rash and exfoliative dermatitis were also reported. Vasculitis has been reported rarely.

Hypersensitivity: As with other H2-receptor antagonists, rare cases of anaphylaxis following administration of Nizatidine have been reported. Rare episodes of hypersensitivity reactions (e.g., bronchospasm, laryngeal edema, rash, and eosinophilia) have been reported.

Body as a Whole: Serum sickness-like reactions have occurred rarely in conjunction with Nizatidine use.

Genitourinary: Reports of impotence have occurred.

Other: Hyperuricemia unassociated with gout or nephrolithiasis was reported. Eosinophilia, fever, and nausea related to Nizatidine administration have been reported.

Overdosage

Overdoses of Nizatidine have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.

Signs and Symptoms

There is little clinical experience with overdosage of Nizatidine in humans. Test animals that received large doses of Nizatidine have exhibited cholinergic-type effects, including lacrimation, salivation, emesis, miosis, and diarrhea. Single oral doses of 800 mg/kg in dogs and of 1200 mg/kg in monkeys were not lethal. Intravenous median lethal doses in the rat and mouse were 301 mg/kg and 232 mg/kg respectively.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

If overdosage occurs, use of activated charcoal, emesis, or lavage should be considered along with clinical monitoring and supportive therapy. The ability of hemodialysis to remove Nizatidine from the body has not been conclusively demonstrated; however, due to its large volume of distribution, Nizatidine is not expected to be efficiently removed from the body by this method.

Nizatidine Dosage and Administration

Active Duodenal Ulcer

The recommended oral dosage for adults is 300 mg once daily at bedtime. An alternative dosage regimen is 150 mg twice daily.

Maintenance of Healed Duodenal Ulcer

The recommended oral dosage for adults is 150 mg once daily at bedtime.

Gastroesophageal Reflux Disease

The recommended oral dosage in adults for the treatment of erosions, ulcerations, and associated heartburn is 150 mg twice daily.

Active Benign Gastric Ulcer

The recommended oral dosage is 300 mg given either as 150 mg twice daily or 300 mg once daily at bedtime. Prior to treatment, care should be taken to exclude the possibility of malignant gastric ulceration.

Dosage Adjustment for Patients With Moderate to Severe Renal Insufficiency

The dose for patients with renal dysfunction should be reduced as follows:

Active Duodenal Ulcer, GERD and Benign Gastric Ulcer
Ccr	Dose
20-50 mL/min	150 mg daily
<20 mL/min	150 mg every other day
Maintenance Therapy
Ccr	Dose
20-50 mL/min	150 mg every other day
<20 mL/min	150 mg every 3 days

 Some elderly patients may have creatinine clearances of less than 50 mL/min, and, based on pharmacokinetic data in patients with renal impairment, the dose for such patients should be reduced accordingly. The clinical effects of t

Niacor

Pronunciation: NYE-a-sin
Generic Name: Niacin
Brand Name: Niacor

Niacor is used for:

Improving cholesterol levels, reducing the risk for a second heart attack, slowing or treating hardening of the arteries, and lowering very high serum triglyceride levels. It is used in combination with diet. It may be used alone or with other medicines. It may also be used for other conditions as determined by your doctor.

Niacor is an antihyperlipidemic. It works by reducing low-density lipoprotein ("bad") cholesterol and triglycerides and increasing high-density lipoprotein ("good") cholesterol.

Do NOT use Niacor if:

• you are allergic to any ingredient in Niacor


• you have severe or unexplained liver problems, an active peptic ulcer, or a history of arterial bleeding

Contact your doctor or health care provider right away if any of these apply to you.

Before using Niacor:

Some medical conditions may interact with Niacor. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of chest pain, diabetes, gallbladder problems, glaucoma, gout, heart problems or a recent heart attack, kidney or liver problems, low blood pressure, low phosphate levels, muscle problems (eg, rhabdomyolysis), stomach problems (eg, peptic ulcers), or thyroid problems


• if you have a history of bleeding problems or are taking anticoagulants (eg, warfarin)


• if you consume large amounts of alcohol

Some MEDICINES MAY INTERACT with Niacor. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin) because side effects such as bleeding may occur


• Fibrates (eg, gemfibrozil, fenofibrate) or HMG-CoA reductase inhibitors ("statins") (eg, simvastatin) because side effects, such as serious muscle aches and weakness that may be a symptom of a serious medical condition called rhabdomyolysis, may occur


• Medicine for high blood pressure (eg, diltiazem) or angina (eg, nitroglycerin) because side effects, such as dizziness upon standing and very low blood pressure, may be increased by Niacor


• Alcohol because toxic effects, such as delirium or lactic acidosis, may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Niacor may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Niacor:

Use Niacor as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• To minimize flushing and upset stomach, take Niacor at bedtime after a low-fat snack (eg, low-fat yogurt, banana, crackers with a glass of milk) unless your doctor directs otherwise. Do not take Niacor with alcohol, a hot drink, or spicy foods.


• Do not take bile acid sequestrants (eg, colestipol, cholestyramine) within 4 to 6 hours of taking Niacor.


• If you miss a dose of Niacor, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Niacor.

Important safety information:

• Niacor may cause dizziness or lightheadedness. These effects may be worse if you take it with alcohol or certain medicines. Use Niacor with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Niacor may cause dizziness; alcohol, hot weather, exercise, or fever may increase this effect. To prevent it, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of this effect.


• Do NOT take more than the recommended dose without checking with your doctor.


• Niacor may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Do not substitute Niacor for any other type of niacin without talking with your doctor. Severe liver damage can occur.


• If you stop taking Niacor for an extended period, contact your doctor before you start taking it again. Your dose may need to be adjusted.


• Flushing occurs with Niacor and may last for several hours. Talk with your doctor if flushing becomes bothersome.


• Take Niacor at bedtime so that flushing will occur during sleep. If you are awakened by flushing at night, get up slowly, especially if you feel dizzy or faint or if you are taking blood thinners. Take aspirin or a nonsteroidal anti-inflammatory drug (NSAID) (eg, ibuprofen) 30 minutes before taking Niacor to lessen flushing.


• Diabetes patients - Niacor may cause the results of some tests for urine glucose to be wrong. Ask your doctor before you change your diet or the dose of your diabetes medicine.


• Do not take large doses of vitamins while you use Niacor unless your doctor tells you to.


• Report any unexplained muscle pain, tenderness, or weakness to your doctor right away, especially if you also have a fever or general body discomfort.


• Niacor may interfere with certain lab tests, including plasma or urinary catecholamine tests or urine glucose tests. Be sure your doctor and lab personnel know you are taking Niacor.


• Lab tests, including liver function tests, blood glucose, and serum creatine kinase tests, may be performed while you use Niacor. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Niacor should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Niacor while you are pregnant. It is not known if Niacor is found in breast milk. Do not breast-feed while taking Niacor.

Possible side effects of Niacor:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness; headache; heartburn; increased cough, indigestion, or upset stomach; nausea; temporary skin redness, itching, tingling, or feelings of warmth (flushing); vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); black, tarry, or bloody stools; changes in vision (eg, cloudy or blurred vision); decrease in urine or dark-colored urine; fainting; fast or irregular heartbeat; flu-like symptoms (eg, chills, fever, persistent sore throat); increased sweating; loss of appetite; muscle pain, tenderness, swelling, or weakness (with or without fever and fatigue); numbness or persistent tingling of the skin; severe dizziness or headache; severe or persistent diarrhea, nausea, or vomiting; shortness of breath; stomach pain; swelling of the hands, legs, or feet; unusual bruising or bleeding; vomit that looks like coffee grounds; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Niacor side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include flushing.

Proper storage of Niacor:

Store Niacor at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Niacor out of the reach of children and away from pets.

General information:

• If you have any questions about Niacor, please talk with your doctor, pharmacist, or other health care provider.


• Niacor is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Niacor. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Niacor resources

• Niacor Side Effects (in more detail)
• Niacor Dosage
• Niacor Use in Pregnancy & Breastfeeding
• Drug Images
• Niacor Drug Interactions
• Niacor Support Group
• 0 Reviews for Niacor - Add your own review/rating

• Niacor nicotinic acid Concise Consumer Information (Cerner Multum)


• Niacor Advanced Consumer (Micromedex) - Includes Dosage Information


• Niacor Prescribing Information (FDA)


• Niacin Monograph (AHFS DI)

Compare Niacor with other medications

• High Cholesterol
• Hyperlipoproteinemia
• Hyperlipoproteinemia Type IV, Elevated VLDL
• Hyperlipoproteinemia Type V, Elevated Chylomicrons VLDL
• Niacin Deficiency
• Pellagra

Stimulin

Stimulin may be available in the countries listed below.

Ingredient matches for Stimulin

Glimepiride

Glimepiride is reported as an ingredient of Stimulin in the following countries:

• Bangladesh

International Drug Name Search

Neo-Synephrine Mild Nasal

Generic Name: phenylephrine nasal (FEN il EFF rin)

Brand Names: 4-Way, 4-Way Menthol, Afrin 4 Hour Extra Moisturizing, Little Noses Decongestant, Neo-Synephrine Extra Strength Nasal, Neo-Synephrine Mild Nasal, Neo-Synephrine Nasal, Sinex Nasal Spray, Sinex Ultra Fine Mist

What is Neo-Synephrine Mild Nasal (phenylephrine nasal)?

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

Phenylephrine nasal is used to treat nasal congestion and sinus pressure caused by allergies, the common cold, or the flu. Phenylephrine may be used to treat congestion of the tubes that drain fluid from your inner ears, called the eustachian (yoo-STAY-shun) tubes.

Phenylephrine nasal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Neo-Synephrine Mild Nasal (phenylephrine nasal)?

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

You should not use this medication if you are allergic to phenylephrine.

Do not use phenylephrine nasal if you have used linezolid (Zyvox) or procarbazine (Matulane), or if you have taken a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life-threatening side effects can occur if you use phenylephrine before these other drugs have cleared from your body.

Before using phenylephrine nasal, tell your doctor if you are allergic to any decongestants, or if you have heart disease, heart rhythm disorder, high blood pressure, diabetes, glaucoma, a thyroid disorder, or an enlarged prostate or urination problems.

Phenylephrine may interact with heart or blood pressure medications, antidepressants, diabetes medications, and other decongestants.

Never use more of this medicine than directed on the label or prescribed by your doctor.

Call your doctor if your symptoms do not improve after 3 days of using phenylephrine nasal, or if they get worse and you also have a fever. Using phenylephrine nasal too long can damage the lining of your nasal passages and lead to chronic nasal congestion.

What should I discuss with my healthcare provider before using Neo-Synephrine Mild Nasal (phenylephrine nasal)?

You should not use this medication if you are allergic to phenylephrine.

Do not use phenylephrine nasal if you have used linezolid (Zyvox) or procarbazine (Matulane), or if you have taken a monoamine oxidase inhibitor (MAOI) such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life-threatening side effects can occur if you use phenylephrine before these other drugs have cleared from your body.

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

• 
  

  heart disease, heart rhythm disorder;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  a thyroid disorder; or

  
  


• 
  

  an enlarged prostate or urination problems.

  
  

FDA pregnancy category C. Is not known whether this medication will harm an unborn baby. Before using phenylephrine nasal, tell doctor if you are pregnant. Phenylephrine nasal may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Older adults may be more likely to have side effects from this medication.

How should I use Neo-Synephrine Mild Nasal (phenylephrine nasal)?

Use 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. Cold medicine should be used only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children.

Phenylephrine nasal is usually used every 4 hours. Follow the directions on the medicine label. Never use more of this medicine than directed on the label or prescribed by your doctor. Using phenylephrine nasal too long can damage the lining of your nasal passages and lead to chronic nasal congestion.

Gently blow your nose to clear any mucus before using this medication.

To use the nasal spray, insert the tip of the spray bottle into your nostril, past the middle of the inside of your nose (the nasal septum). Gently press your other nostril closed with your finger.

Keep your head upright, and squeeze the bottle while breathing in deeply through your nose. Sniff quickly a few times to get the medicine deep into your nasal passages.

Repeat these steps to use the medicine in your other nostril if needed.

After each use, clean the tip of the spray bottle with a clean tissue or rinse it with hot water, making sure that no water gets into the medicine bottle. Keep the cap on the bottle when not in use.

To use the nasal drops, lie on your back with your head tilted back. Insert the correct number of drops and remain lying in this position for several minutes. Gently turn your head from side to side.

Call your doctor if your symptoms do not improve after 3 days of using phenylephrine nasal, or if they get worse and you also have a fever.

If you need to have any type of surgery, tell the surgeon ahead of time if you have used phenylephrine nasal within the past few days.

Store at room temperature away from moisture and heat. To prevent the spread of infection, do not share this medication with anyone else.

What happens if I miss a dose?

Since phenylephrine nasal is usually used only when needed, you may not be on a dosing schedule. If you are using the medication regularly, use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe dizziness or drowsiness, slow heart rate, and fainting.

What should I avoid while using Neo-Synephrine Mild Nasal (phenylephrine nasal)?

Avoid getting this medication in your eyes. Ask a doctor or pharmacist before using any other cold, cough, or allergy medicine. Phenylephrine is contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains phenylephrine.

Neo-Synephrine Mild Nasal (phenylephrine nasal) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using phenylephrine and call your doctor at once if you have a serious side effect such as:

• 
  

  severe sneezing, runny or stuffy nose, redness or swelling in your nose, or other worsening nasal symptoms (may be a sign of overuse of phenylephrine nasal);

  
  


• 
  

  severe stinging, burning, or irritation inside your nose;

  
  


• 
  

  severe dizziness, restless feeling, nervousness, or insomnia;

  
  


• 
  

  mood changes, unusual thoughts or behavior;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  slow, fast, or pounding heartbeat;

  
  


• 
  

  tremors or shaking; or

  
  


• 
  

  urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  temporary sneezing;

  
  


• 
  

  mild burning, dryness, cold feeling, or irritation inside your nose;

  
  


• 
  

  headache, dizziness, weakness;

  
  


• 
  

  sweating, nausea;

  
  


• 
  

  feeling excited or restless (especially in children); or

  
  


• 
  

  mild sleep problems.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Neo-Synephrine Mild Nasal (phenylephrine nasal)?

Tell your doctor about all other medications you use, especially:

• 
  

  other decongestants;

  
  


• 
  

  medicine to treat diabetes;

  
  


• 
  

  medicines to treat high blood pressure such as reserpine, guanethidine (Ismelin), methyldopa (Aldomet), and others; or

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

This list is not complete and other drugs may interact with phenylephrine nasal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Neo-Synephrine Mild Nasal resources

• Neo-Synephrine Mild Nasal Use in Pregnancy & Breastfeeding
• Neo-Synephrine Mild Nasal Drug Interactions
• Neo-Synephrine Mild Nasal Support Group
• 0 Reviews for Neo-Synephrine Nasal - Add your own review/rating

• Rhinall Advanced Consumer (Micromedex) - Includes Dosage Information


• Rhinall Solution MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Neo-Synephrine Mild Nasal with other medications

• Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about phenylephrine nasal.

Zamadol SR Capsules 50mg, 100mg, 150mg, 200mg

1. Name Of The Medicinal Product

Zamadol SR 50 mg prolonged-release hard capsules

Zamadol SR 100 mg prolonged-release hard capsules

Zamadol SR 150 mg prolonged-release hard capsules

Zamadol SR 200 mg prolonged-release hard capsules

2. Qualitative And Quantitative Composition

One capsule contains 50 mg, 100mg, 150mg, 200mg of tramadol hydrochloride

This product contains the excipients sucrose (9.375 18.75 28.125 37.5mg/capsule).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release hard capsule.

The 50 mg capsules are dark green and marked T50SR.

The 100 mg capsules are white and marked T100SR

The 150 mg capsules are dark green and marked T150SR

The 200 mg capsules are yellow and marked T200SR

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of moderate to severe pain.

4.2 Posology And Method Of Administration

The capsules are intended for twice daily oral administration and can be taken independently of meal times, swallowed whole with water.

As with all analgesic drugs the dosing of Zamadol SR prolonged-release hard capsules should be adjusted depending on the severity of the pain and the individual clinical response of the patient. The dose used should be the lowest dose that provides pain relief.

Adults:

The usual initial dose is 50-100 mg twice daily, morning and evening. This dose may be titrated up to 150-200 mg twice daily according to pain severity.

If long-term pain treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

A total oral daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Elderly patients:

Dosing as for adults, however it should be noted that in patients over 75 years there tends to be an increase in absolute bioavailability of tramadol and a 17% increase in the terminal elimination half-life. An adjustment of the dosage or the dose interval may be required.

Patients with renal or hepatic insufficiency:

As the elimination of tramadol may be prolonged in patients with severe renal and/or hepatic impairment, the use of Zamadol SR prolonged-release hard capsulesis not recommended. In moderate cases an adjustment of the dosage interval may be required.

Patients who have difficulty in swallowing:

Zamadol SR prolonged-release hard capsules can be opened, carefully, so that the pellets are deposited on a spoon. The spoon and pellets should be taken into the mouth, followed by a drink of water to rinse the mouth of all pellets. The pellets must not be chewed or crushed.

Children and adolescents :

Over 12 years: Dosage as for adults.

Under 12 years: Zamadol SR prolonged-release hard capsules have not been studied in children. Therefore, safety and efficacy have not been established and the product should not be used in children.

4.3 Contraindications

Zamadol SR prolonged-release hard capsules should not be given to patients who have previously shown hypersensitivity to the active substance tramadol or to any of the other excipients.

The product should not be administered to patients suffering from acute intoxication with hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol.

Tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within 2 weeks of their withdrawal.

Contra-indicated in patients suffering from uncontrolled epilepsy.

Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special Warnings And Precautions For Use

Warnings:

Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should be for short periods under strict medical supervision. In rare cases at therapeutic doses, tramadol has the potential to cause withdrawal symptoms.

Zamadol SR prolonged-release hard capsules are not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5).

This medicinal product contains sucrose and therefore should not be used by patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Precautions:

Zamadol SR prolonged-release hard capsules should be used with prudence in patients who have shown previous hypersensitivity to opiates, and in patients with severe renal or hepatic impairment, head injury, decreased level of consciousness, increased intracranial pressure, or patients in shock or at risk of convulsions.

At recommended therapeutic doses Zamadol SR prolonged-release hard capsules are unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering Zamadol SR prolonged-release hard capsules to patients with existing respiratory depression or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Patients treated with monoamine oxidase inhibitors within 14 days prior to the administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.

Tramadol may potentiate the CNS depressant effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs.

Tramadol may increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions (see section 4.4).

Isolated cases of serotonergic syndrome have been reported with the therapeutic use of tramadol in combination with other serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs). Serotonergic syndrome can be manifested by symptoms such as confusion, restlessness, fever, sweat, ataxia, hyperreflexia, myoclonia and diarrhoea. Withdrawal of the serotonergic agent produces a rapid improvement.

Administration of Zamadol SR prolonged-release hard capsules together with carbamazepine results in markedly decreased serum concentrations of tramadol which may reduce analgesic effectiveness and shorten the duration of action.

Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients.

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirements of tramadol in patients with postoperative pain.

There is no interaction with food.

4.6 Pregnancy And Lactation

Pregnancy:

Zamadol SR prolonged-release hard capsules should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol - administered before or during birth - does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant.

Lactation:

Zamadol SR prolonged-release hard capsules should not be administered during breast feeding as tramadol and its metabolites have been detected in breast milk. 0.1% of the dose administered to the mother may be excreted in milk.

4.7 Effects On Ability To Drive And Use Machines

Zamadol SR prolonged-release hard capsules may cause drowsiness and this effect may be potentiated by alcohol, anti-histamines and other CNS depressants. If patients are affected they should be warned not to drive or operate machinery.

4.8 Undesirable Effects

The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.

Immune system disorders:

Rare (

Metabolism and nutrition disorders:

Rare (

Psychiatric disorders:

Rare (1/10,000 to < 1/1,000): psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders), hallucinations, confusion, sleep disturbances and nightmares.

Prolonged administration of Zamadol SR prolonged-release hard capsules may lead to dependence (see section 4.4). Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Nervous system disorders:

Very common (1/10) dizziness.

Common (

Rare (

Paraesthesia and tremor.

Very rare (< 1/10,000): vertigo

Eye disorders:

Rare (

Cardiac disorders:

Uncommon (1/1,000 to < 1/100): effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially on intravenous administration and in patients who are physically stressed.

Rare (1/10,000 to < 1/1,000): bradycardia, increase in blood pressure.

Vascular disorders:

Very rare (< 1/10,000): flushing.

Respiratory disorders:

Worsening of asthma has also been reported, though a causal relationship has not been established.

Respiratory depression has been reported. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5 "Interaction with other medicinal products and other forms of interaction") respiratory depression may occur.

Gastrointestinal disorders:

Very common (1/10): vomiting, nausea.

Common (1/100 to < 1/10): constipation, dry mouth.

Uncommon (1/1,000 to < 1/100): retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).

Hepatobiliary disorders:

In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.

Skin and subcutaneous tissue disorders:

Common (1/100 to < 1/10): sweating.

Uncommon (1/1,000 to < 1/100): dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders:

Rare (1/10,000 to < 1/1,000): motorial weakness.

Renal and urinary system disorders:

Rare (1/10,000 to < 1/1,000): micturition disorders (difficulty in passing urine and urinary retention).

General disorders:

Common (

4.9 Overdose

Symptoms of tramadol overdose include vomiting, miosis, sedation, seizures, respiratory depression and hypotension, with circulatory failure and coma. Respiratory failure may also occur. Such symptoms are typical of opioid analgesics.

Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Respiratory depression may be reversed using naloxone and fits controlled with diazepam. Naloxone administration may increase the risk of seizures.

The treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not sufficient or suitable due to the slow elimination of tramadol from the serum by these routes.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other opioids, ATC code: N02AX02

Tramadol is a centrally acting analgesic which possesses opioid agonist properties. Tramadol consists of two enantiomers, the (+)-isomer is predominantly active as an opioid with preferential activity for the μ-receptor. The (-)-isomer potentiates the analgesic effect of the (+)-isomer and is active as an inhibitor of noradrenaline and serotoninuptake thereby modifying the transmission of pain impulses.

Tramadol also has an antitussive action. At the recommended dosages, the effects of tramadol given orally on the respiratory and cardiovascular systems appear to be clinically insignificant. The potency of tramadol is reported to be 1/10 to 1/6 of morphine.

5.2 Pharmacokinetic Properties

About 90% of tramadol released from Zamadol SR prolonged-release hard capsules is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of concomitant intake of food.

The difference between absorbed and non-metabolised available tramadol is probably due to low first-pass effect. The first pass-effect after oral administration is a maximum of 30%.

Tramadol has a high tissue affinity with an apparent volume of distribution of 203 ± 40 litres after oral dosing in healthy volunteers. Protein binding is limited to 20%.

After single dose administration of Zamadol SR 50 mg prolonged-release hard capsules the peak plasma concentration C_max 70 ± 16 ng/ml is reached after 5.3 h. After administration of Zamadol SR 100 mg prolonged-release hard capsules C_max 137 ± 27 ng/ml is reached after 5.9 h. Following administration of Zamadol SR 200 mg prolonged-release hard capsules C_max 294 ± 82 ng/ml is reached after 6.5 h. The reference product (Tramadol Immediate Release Capsules, given as a total dose of 200 mg tramadol hydrochloride) reached a peak concentration of C_max 640 ± 143 ng/ml after 2.0 hours.

The relative bioavailability for the slow release formulation after single dose administration is 89% and increases to 100% after multiple dose administration in comparison to the reference product.

Tramadol passes the blood-brain and placenta barriers. Very small amounts of the substance and its O-demethyl derivative are found in the breast-milk (0.1% and 0.02% respectively of the applied dose).

Elimination of half-life t_½βis approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of 1.4.

In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half life t_½β (6 healthy volunteers) is 7.9 h (range 5.4-9.6 h) and is approximately that of tramadol.

The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.

Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively have been determined. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.

Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100 - 300 ng/ml is usually effective.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. Studies of tramadol in rats and rabbits have revealed no teratogenic effects. However, embryo toxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule Contents: Sugar spheres (sucrose and maize starch), colloidal anhydrous silica, ethylcellulose, shellac, talc.

Capsule Shell: Gelatin, Titanium Dioxide (E171)

The 50 mg and 150 mg capsules also contain Iron Oxide Yellow (E172) and Indigotine (E132).

The 200 mg capsules also contain Iron Oxide Yellow (E172)

Printing ink contains shellac, iron oxide black (E172) and propylene glycol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

White opaque PVC/PVDC and aluminium foil blisters. Each blister contains 10 capsules.

Each pack contains 10, 20, 30, 50, 60 or 100 capsules per pack.

Not all pack sizes may be marketed in all Member States.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

8. Marketing Authorisation Number(S)

PL 15142/0120

PL 15142/0121

PL 15142/0122

PL 15142/0123

9. Date Of First Authorisation/Renewal Of The Authorisation

September 2007

10. Date Of Revision Of The Text

10 September 2009