NovoSeven RT

Generic Name: coagulation factor viia (Intravenous route)

koh-a-gyoo-LAY-shun FAK-tor SEV-en A

Intravenous route(Powder for Solution)

Serious arterial and venous thrombotic and thromboembolic adverse events, including fatalities, are associated with the use of coagulation factor VIIa when used outside labeling indications. Patients should be advised and monitored on the signs/symptoms of thrombotic and thromboembolic events .

Commonly used brand name(s)

In the U.S.

• Novoseven


• NovoSeven RT

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Hemostatic

Uses For NovoSeven RT

Factor VIIa is used to treat and prevent bleeding episodes in patients with Hemophilia A or B who have formed antibodies against other clotting proteins (e.g., Factor VIII or Factor IX) that help bleeding to stop. It is also used to treat or prevent bleeding in patients with acquired hemophilia or congenital Factor VII deficiency.

Factor VIIa is a man-made protein produced to replicate the naturally occurring activated factor VII (factor VIIa) in the body. It is used to stop bleeding of injuries for patients with hemophilia by helping the blood to clot.

Factor VIIa is to be administered only by or under the supervision of your doctor or other health care professional.

Before Using NovoSeven RT

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Factor VIIa in children.

Geriatric

Adequate and well-controlled studies have not been done on the relationship of age to the effects of Factor VIIa in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clots or a history of medical problems caused by blood clots or


• Heart disease or


• Infection or


• Injury (crush)—These conditions may increase the risk of developing blood clots.

Proper Use of coagulation factor viia

This section provides information on the proper use of a number of products that contain coagulation factor viia. It may not be specific to NovoSeven RT. Please read with care.

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins.

Precautions While Using NovoSeven RT

It is very important that your doctor check your progress closely while you are receiving this medicine to make sure it is working properly. Blood tests may be needed to check for unwanted effects.

If you notice early signs of a hypersensitivity reaction such as hives, skin rash, tightness of the chest or wheezing, lightheadedness or dizziness, notify your physician immediately.

This medicine may increase your chance of having blood clotting problems. Tell your doctor right away if you have sudden or severe headache, problems with vision or speech, chest pain, shortness of breath, or numbness or weakness while you are receiving this medicine.

NovoSeven RT Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Bleeding problems


• fever


• high blood pressure


• joint or muscle pain and/or stiffness

Less common or rare

• Bloating or swelling of the face, hands, lower legs, and/or feet


• bluish color of the hands or feet


• blurred vision


• changes in facial color


• chest pain


• chills


• cold sweats


• confusion


• continuing thirst


• cough


• dizziness


• excessive sweating


• faintness


• fast heartbeat


• hives and/or itching


• large flat blue or purplish patches on the skin


• lightheadedness when getting up from a lying or sitting position suddenly


• persistent bleeding or oozing from puncture sites or mucous membranes (bowel, mouth, nose, or urinary bladder)


• puffiness or swelling of the eyelids or around the eyes


• shakiness


• shortness of breath


• skin rash


• slow or irregular heartbeat (less than 50 beats per minute)


• slurred speech


• sneezing


• sore throat


• sudden decrease in the amount of urine


• swelling of the face, fingers, feet, and/or lower legs


• troubled breathing, tightness in the chest, and/or wheezing


• unusual tiredness or weakness


• weight gain (unusual)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common or rare

• Burning or stinging at the injection site


• changes in the blood pressure or pulse rate


• drowsiness


• flushing (redness of the face)


• headache


• nausea or vomiting


• pinpoint red or purple spots on the skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: NovoSeven RT side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More NovoSeven RT resources

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

• NovoSeven RT Prescribing Information (FDA)


• NovoSeven RT injection Concise Consumer Information (Cerner Multum)


• NovoSeven RT Monograph (AHFS DI)


• NovoSeven RT MedFacts Consumer Leaflet (Wolters Kluwer)


• Novoseven MedFacts Consumer Leaflet (Wolters Kluwer)

Compare NovoSeven RT with other medications

• Factor VII Deficiency
• Hemophilia A
• Hemophilia B

Nizatidine Solution

Nizatidine Oral Solution

Rx only

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 331.47. It is an off-white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor.

Nizatidine Oral Solution is formulated as a clear, yellow, oral solution with bubble gum flavor and each 1 mL contains 15 mg of nizatidine. Nizatidine Oral Solution also contains the inactive ingredients methylparaben, propylparaben, glycerin, sodium alginate, purified water, sodium chloride, saccharin sodium, sodium citrate dihydrate, citric acid anhydrous, sucrose, bubble gum flavor, artificial sweetness enhancer, and sodium hydroxide.

Clinical Pharmacology in Adults:

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

Antisecretory Activity—

1. 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

2. Effects on Other Gastrointestinal Secretions—Pepsin: Oral administration of 75 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 to 300 mg of nizatidine increased betazole-stimulated secretion of intrinsic factor.

Serum Gastrin Concentration: 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.

3. Other Pharmacologic Actions—

1. Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodo-thyronine, thyroxin, testosterone, 5 α-dihydro-testos terone, androstenedione, or estradiol.


2. Nizatidine had no demonstrable antiandrogenic action.

4. Pharmacokinetics—The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 μg/L for a 150-mg dose and 1,400 to 3,600 μg/L for a 300-mg dose) occur from 0.5 to 3 hours following the dose. Plasma concen trations 12 hours after administration are less than 10 μg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 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 anticholinergic 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-monodes methylnizatidine, 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 orally administered 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 pro longs 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 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.

At a dose of 150 mg, the Nizatidine Oral Solution (15 mg/mL) is bioequivalent to nizatidine capsules.

Clinical Pharmacology in Pediatric Patients:

Pharmacokinetics

Table 2 presents pharmacokinetic data of nizatidine administered orally to adolescents with gastroesophageal reflux (GER) and healthy adults. Pharmacokinetic parameters for adolescent patients ages 12 to 18 years are comparable to those obtained for adults.

Table 2. Pharmacokinetics of Oral Nizatidine

SD=single dose SS=steady state
			Cmax	Tmax	AUCo-∞	CLF	VdF	T1/2
Age Range	Formulation	Dose	(ng/mL)	(h)	(ng•h/mL)	(L/h)	(L)	(h)
12-18 yr	Capsule	150 mg SD	1422.9	1.3	3764.2	41.0	71.4	1.2
Adolescents		150 mg SS	1480.2	1.4	3776.1	41.1	74.2	1.3
with GER
Healthy	Capsule	150 mg SD	1367.6	1.0	3703.1	41.9	83.4	1.4
Adults	Oral Solution	150 mg SD	1340.6	0.8	3610.9	43.0	86.4	1.4
	Apple Juice	150 mg SD	762.8	1.3	2694.1	57.5	142.3	1.7

Administration of nizatidine capsules in apple juice results in 27% reduction of nizatidine bioavailability.

Pharmacodynamics

Pharmacodynamics of nizatidine were evaluated in 48 pediatric patients. These data suggest that gastric acid suppression is similar to that observed in adult studies (Table 3).

Table 3. Pharmacodynamics of Oral Nizatidine

Age	% Time	% Time	AUEC0-12h
	pH>3	pH >4	(pH•h)
12-18 years	57	42	41.4
Adults	31	19	34.8

Clinical Trials (Adults)—

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 4). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.

Table 4. 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	Healed/	Number	Healed/	Number	Healed/
	Entered	Evaluable	Entered	Evaluable	Entered	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 multicenter, 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 5).

Table 5. 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 con sumed 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 6).

Table 6.

*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:

Nizatidine Oral Solution is indicated for up to 8 weeks for the treatment of active duodenal ulcer. In most patients, the ulcer will heal within 4 weeks.

Nizatidine Oral Solution is 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 for longer than 1 year are not known.

Nizatidine Oral Solution is 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 Oral Solution is 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.

In pediatric patients, Nizatidine Oral Solution is indicated for ages 12 years and older. Nizatidine Oral Solution is indicated for up to 8 weeks for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis, and associated heartburn due to GERD.

Contraindication:

Nizatidine Oral Solution is contraindicated in patients with known hypersensitivity to the drug. Because cross-sen sitivity in this class of compounds has been observed, H2-receptor antagonists, including nizatidine, should not be admini stered 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 (3,900 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 13 times the recommended human dose based on body surface area) 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 (2,000 mg/kg/day, about 27 times the recommended human dose based on body surface area) 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 5 times the recommended human dose based on body surface area), 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 (about 17.5 times the recommended human dose based on body surface area) 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 (about 40.5 times the recommended human dose based on body surface area) and in pregnant rabbits at doses up to 275 mg/kg/day (about 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—Effectiveness in pediatric patients <12 years of age has not been established. Use of nizatidine in pediatric patients from 12 to 18 years of age is supported by evidence from published pediatric literature, adequate and well-controlled published studies in adults, and by the following adequate and well-controlled studies in pediatric patients: (see DOSAGE AND ADMINISTRATION)

Clinical Trials (Pediatric)

. In randomized studies, nizatidine was administered to pediatric patients for up to eight weeks, using age appropriate formulations. A total of 230 pediatric patients from 2 to 18 years of age were administered nizatidine at a dose of either 2.5 mg/kg b.i.d, or 5.0 mg/kg b.i.d, (patients 12 years and under) or 150 mg b.i.d (12 to 18 years). Patients were required to have either symptomatic, clinically suspected or endoscopically diagnosed GERD with age-relevant symptoms. In patients 2 to 18 years of age, nizatidine was found generally safe and well-tolerated. In these studies in patients 12 years and older, nizatidine was found to reduce the severity and frequency of GERD symptoms, improve physical well-being, and reduce the frequency of supplemental antacid consumption. No efficacy in pediatric patients <12 years of age has been established. Clinical studies in patients 2 to 12 years of age with GERD, demonstrated no difference in either symptom improvements or healing rates between nizatidine and placebo or between different doses of nizatidine.

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 in Adults:

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 7 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 non-drug factors to the side-effect incidence rate in the population studied.

Table 7. 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			Percentage of
	Patients Reporting			Patients Reporting
	Event			Event
Body System/	Nizatidine	Placebo	Body System/	Nizatidine	Placebo
Adverse Event*	(N=2,694)	(N=1,729)	Adverse Event*	(N=2,694)	(N=1,729)
Body as a Whole			Nervous
Headache	16.6	15.6	Dizziness	4.6	3.8
Pain	4.2	3.8	Insomnia	2.7	3.4
Asthenia	3.1	2.9	Abnormal dreams	1.9	1.9
Chest pain	2.3	2.1	Somnolence	1.9	1.6
Infection	1.7	1.1	Anxiety	1.8	1.4
Injury, accident	1.2	0.9	Nervousness	1.1	0.8
Digestive			Respiratory
Diarrhea	7.2	6.9	Rhinitis	9.8	9.6
Dry mouth	1.4	1.3	Pharyngitis	3.3	3.1
Tooth disorder	1.0	0.8	Sinusitis	2.4	2.1
Musculoskeletal			Cough, increased	2.0	2.0
Myalgia	1.7	1.5	Skin and Appendages
			Rash	1.9	2.1
			Pruritis	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 2,000 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 individua

Levocarnitine Oral Solution

Levocarnitine Oral Solution USP

(1 g per 10 mL multidose)

Levocarnitine Oral Solution Description

Levocarnitine is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane.

The chemical name of levocarnitine is 3-carboxy- 2(R)-hydroxy- N , N , N - t r i m e t h y l - 1 - propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is:

Empirical Formula: C7H15NO3 Molecular Weight: 161.20

Each 118 mL container of Levocarnitine Oral Solution USP contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sucrose Syrup, Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5.

Levocarnitine Oral Solution - Clinical Pharmacology

Levocarnitine is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production.

Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with levocarnitine. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. Levocarnitine may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria ll, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be lifethreatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/ levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations.

PHARMACOKINETICS

In a relative bioavailability study in 15 healthy adult male volunteers, Ievocarnitine tablets were found to be bio-equivalent to Levocarnitine Oral Solution. Following 4 days of dosing with 6 tablets of levocarnitine 330 mg b.i.d. or 2 g of Levocarnitine Oral Solution b.i.d, the maximum plasma concentration (Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.

The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of levocarnitine were described by a twocompartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.

The absolute bioavailability of levocarnitine from the two oral formulations of levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for levocarnitine tablets and 15.9 ± 4.9% for Levocarnitine Oral Solution.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h.

Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9

METABOLISM AND EXCRETION

In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-Lcarnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10

After attainment of steady state following 4 days of oral administration of levocarnitine tablets (1980 mg q12h) or oral solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

Indications and Usage for Levocarnitine Oral Solution

Levocarnitine is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.

Levocarnitine is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency.

Contraindications

None known.

Warnings

None.

Precautions

General

Levocarnitine Oral Solution USP is for oral/internal use only.

Not for parenteral use.

Gastrointestinal reactions may result from a too rapid consumption of carnitine. Levocarnitine Oral Solution USP may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance.

The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenecity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.

Pregnancy

Pregnancy Category B.

Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to levocarnitine. 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

Levocarnitine supplementation in nursing mothers has not been specifically studied.

Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.

Pediatric Use

See Dosage and Administration.

Adverse Reactions

Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with Levocarnitine Oral Solution USP dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.

Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.

Overdosage

There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

Levocarnitine Oral Solution Dosage and Administration

Levocarnitine Oral Solution USP

For oral use only. Not for parenteral use.

Adults:

The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of Levocarnitine Oral Solution USP. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.

Infants and children:

The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day Levocarnitine Oral Solution USP. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.

Levocarnitine Oral Solution USP may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance.

How is Levocarnitine Oral Solution Supplied

Levocarnitine Oral Solution USP is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 50383- 171-04). Store at controlled room temperature (25°C). See USP. Levocarnitine Oral Solution USP is distributed and manufactured by Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701.

Rx only.

REFERENCES

1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61.

2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine induced effects on cardiac and peripheral hemodynamics. J. Clin, Pharmacol. 17:561-568.

3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver- cells, Biochim. Biophys. Acta 448:562-577.

4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702.

5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Prac. 58:533-540.

6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66

7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill.

8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.

9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassanni, E. and Solbiati, M. 1991. Protein binding of Lcarnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue lll: 364- 368,

10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305- 1310.

Distributed and manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

PREVIOUS EDITION IS OBSOLETE

Date of Issue: 10/04

GOPI-1

MG #20589

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 50383-171-04

Levocarnitine Oral Solution USP

 

Active Ingredient: L-carnitine 1 g/10 mL

Inactive Ingredients: Artificial Cherry Flavor, D, L-Malic Acid, Methylparaben NF, Propylparaben NF, Purified Water, Sucrose Syrup.

DOSAGE: See package insert.

 

118 mL (4 fl. oz.)

Multiple Unit Container

Rx only

LEVOCARNITINE  levocarnitine  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50383-171 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVOCARNITINE (LEVOCARNITINE) LEVOCARNITINE 1 g  in 10 mL

Inactive Ingredients Ingredient Name Strength CHERRY   MALIC ACID   WATER   SUCROSE   METHYLPARABEN   PROPYLPARABEN

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 50383-171-04 118 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA077399	10/25/2007

Labeler - Hi-Tech Pharmacal Co., Inc. (101196749)

Establishment
Name	Address	ID/FEI	Operations
Hi-Tech Pharmacal Co., Inc.		101196749	MANUFACTURE

Revised: 08/2010Hi-Tech Pharmacal Co., Inc.

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Nascobal

cyanocobalamin

Dosage Form: nasal spray
Nascobal®

Nasal spray

(Cyanocobalamin, USP)

500 mcg/spray

Nascobal Description

Cyanocobalamin is a synthetic form of vitamin B12 with equivalent vitamin B12 activity. The chemical name is 5,6-dimethyl-benzimidazolyl cyanocobamide. The cobalt content is 4.35%. The molecular formula is C63H88CoN14O14P, which corresponds to a molecular weight of 1355.38 and the following structural formula:

Cyanocobalamin occurs as dark red crystals or orthorhombic needles or crystalline red powder. It is very hygroscopic in the anhydrous form, and sparingly to moderately soluble in water (1:80). Its pharmacologic activity is destroyed by heavy metals (iron) and strong oxidizing or reducing agents (vitamin C), but not by autoclaving for short periods of time (15-20 minutes) at 121°C. The vitamin B12 coenzymes are very unstable in light.

Nascobal Nasal Spray is a solution of Cyanocobalamin, USP (vitamin B12) for administration as a spray to the nasal mucosa. Each bottle of Nascobal Nasal Spray contains 1.3mL of a 500 mcg/0.1mL solution of cyanocobalamin with sodium citrate, citric acid, and glycerin and benzalkonium chloride in purified water. The spray solution has a pH between 4.5 and 5.5. The spray pump unit must be fully primed (see Dosage and Administration) prior to initial use. After initial priming, each spray delivers an average of 500 mcg of cyanocobalamin and the 1.3mL of spray solution contained in the bottle will deliver 4 doses of Nascobal Nasal Spray. The unit must be re-primed before each dose. (see Dosage and Administration).

CLINICAL PHARMACOLOGY

GENERAL PHARMACOLOGY AND MECHANISM OF ACTION

Vitamin B12 is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (e.g., epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for vitamin B12. Vitamin B12 can be converted to coenzyme B12 in tissues, and as such is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine, a reaction which also requires folate. In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyltetrahydrofolate, and a functional folate deficiency occurs. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage that begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head.

Cyanocobalamin is the most stable and widely used form of vitamin B12, and has hematopoietic activity apparently identical to that of the antianemia factor in purified liver extract. The information below, describing the clinical pharmacology of cyanocobalamin, has been derived from studies with injectable vitamin B12.

Vitamin B12 is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of injection. It is bound to plasma proteins and stored in the liver. Vitamin B12 is excreted in the bile and undergoes some enterohepatic recycling. Absorbed vitamin B12 is transported via specific B12 binding proteins, transcobalamin I and II, to the various tissues. The liver is the main organ for vitamin B12 storage.

Parenteral (intramuscular) administration of vitamin B12 completely reverses the megaloblastic anemia and GI symptoms of vitamin B12 deficiency; the degree of improvement in neurologic symptoms depends on the duration and severity of the lesions, although progression of the lesions is immediately arrested.

Gastrointestinal absorption of vitamin B12 depends on the presence of sufficient intrinsic factor and calcium ions. Intrinsic factor deficiency causes pernicious anemia, which may be associated with subacute combined degeneration of the spinal cord. Prompt parenteral administration of vitamin B12 prevents progression of neurologic damage.

The average diet supplies about 4 to 15 mcg/day of vitamin B12 in a protein-bound form that is available for absorption after normal digestion. Vitamin B12 is not present in foods of plant origin, but is abundant in foods of animal origin. In people with normal absorption, deficiencies have been reported only in strict vegetarians who consume no products of animal origin (including no milk products or eggs).

Vitamin B12 is bound to intrinsic factor during transit through the stomach; separation occurs in the terminal ileum in the presence of calcium, and vitamin B12 enters the mucosal cell for absorption. It is then transported by the transcobalamin binding proteins. A small amount (approximately 1% of the total amount ingested) is absorbed by simple diffusion, but this mechanism is adequate only with very large doses. Oral absorption is considered too undependable to rely on in patients with pernicious anemia or other conditions resulting in malabsorption of vitamin B12.

Colchicine, para-aminosalicylic acid, and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B12.

PHARMACOKINETICS

Absorption

A three way crossover study in 25 fasting healthy subjects was conducted to compare the bioavailability of the B12 nasal spray to the B12 nasal gel and to evaluate the relative bioavailability of the nasal formulations as compared to the intramuscular injection. The peak concentrations after administration of intranasal spray were reached in 1.25 +/- 1.9 hours. The average peak concentration of B12 obtained after baseline correction following administration of intranasal spray was 757.96 +/- 532.17 pg/mL. The bioavailability of the nasal spray relative to the intramuscular injection was found to be 6.1%. The bioavailability of the B12 nasal spray was found to be 10% less than the B12 nasal gel. The 90% confidence intervals for the loge-transformed AUC(0-t) and Cmax was 71.71% - 114.19% and 71.6% - 118.66% respectively.

In pernicious anemia patients, once weekly intranasal dosing with 500 mcg B12 gel resulted in a consistent increase in pre-dose serum B12 levels during one month of treatment (p < 0.003) above that seen one month after 100 mcg intramuscular dose (Figure).

Distribution

In the blood, B12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is distributed and stored primarily in the liver and bone marrow.

Elimination

About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; in normal subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When B12 is administered in doses which saturate the binding capacity of plasma proteins and the liver, the unbound B12 is rapidly eliminated in the urine. Retention of B12 in the body is dose-dependent. About 80-90% of an intramuscular dose up to 50 mcg is retained in the body; this percentage drops to 55% for a 100 mcg dose, and decreases to 15% when a 1000 mcg dose is given.

Figure. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses.

INDICATIONS AND USAGE

Nascobal Nasal Spray is indicated for the maintenance of normal hematologic status in pernicious anemia patients who are in remission following intramuscular vitamin B12 therapy and who have no nervous system involvement.

Nascobal Nasal Spray is also indicated as a supplement for other vitamin B12 deficiencies, including:

   I. Dietary deficiency of vitamin B12 occurring in strict vegetarians (Isolated vitamin B12 deficiency is very rare).

   II. Malabsorption of vitamin B12 resulting from structural or functional damage to the stomach, where intrinsic factor is secreted, or to the ileum, where intrinsic factor facilitates vitamin B12 absorption. These conditions include HIV infection, AIDS, Crohn's disease, tropical sprue, and nontropical sprue (idiopathic steatorrhea, gluten-induced enteropathy). Folate deficiency in these patients is usually more severe than vitamin B12 deficiency.

   III. Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric mucosa (ingestion of corrosives, extensive neoplasia), and a number of conditions associated with a variable degree of gastric atrophy (such as multiple sclerosis, HIV infection, AIDS, certain endocrine disorders, iron deficiency, and subtotal gastrectomy). Total gastrectomy always produces vitamin B12 deficiency. Structural lesions leading to vitamin B12 deficiency include regional ileitis, ileal resections, malignancies, etc.

   IV. Competition for vitamin B12 by intestinal parasites or bacteria. The fish tapeworm (Diphyllobothrium latum) absorbs huge quantities of vitamin B12 and infested patients often have associated gastric atrophy. The blind loop syndrome may produce deficiency of vitamin B12 or folate.

   V. Inadequate utilization of vitamin B12. This may occur if antimetabolites for the vitamin are employed in the treatment of neoplasia.

Requirements of vitamin B12 in excess of normal (due to pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic and renal disease) can usually be met with intranasal or oral supplementation.

Nascobal Nasal Spray is not suitable for vitamin B12 absorption test (Schilling Test).

CONTRAINDICATION

Sensitivity to cobalt and/or vitamin B12 or any component of the medication is a contraindication.

Warnings

Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with vitamin B12 suffered severe and swift optic atrophy.

Hypokalemia and sudden death may occur in severe megaloblastic anemia which is treated intensely with vitamin B12. Folic acid is not a substitute for vitamin B12 although it may improve vitamin B12-deficient megaloblastic anemia. Exclusive use of folic acid in treating vitamin B12-deficient megaloblastic anemia could result in progressive and irreversible neurologic damage.

Anaphylactic shock and death have been reported after parenteral vitamin B12 administration. No such reactions have been reported in clinical trials with Nascobal Nasal Spray or Nascobal Nasal Gel.

Blunted or impeded therapeutic response to vitamin B12 may be due to such conditions as infection, uremia, drugs having bone marrow suppressant properties such as chloramphenicol, and concurrent iron or folic acid deficiency.

Precautions

1. GENERAL

An intradermal test dose of parenteral vitamin B12 is recommended before Nascobal Nasal Spray is administered to patients suspected of cyanocobalamin sensitivity. Vitamin B12 deficiency that is allowed to progress for longer than three months may produce permanent degenerative lesions of the spinal cord. Doses of folic acid greater than 0.1 mg per day may result in hematologic remission in patients with vitamin B12 deficiency. Neurologic manifestations will not be prevented with folic acid, and if not treated with vitamin B12, irreversible damage will result.

Doses of vitamin B12 exceeding 10 mcg daily may produce hematologic response in patients with folate deficiency. Indiscriminate administration may mask the true diagnosis.

The validity of diagnostic vitamin B12 or folic acid blood assays could be compromised by medications, and this should be considered before relying on such tests for therapy.

Vitamin B12 is not a substitute for folic acid and since it might improve folic acid deficient megaloblastic anemia, indiscriminate use of vitamin B12 could mask the true diagnosis.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic to normal erythropoiesis with vitamin B12 therapy. Therefore, serum potassium levels and the platelet count should be monitored carefully during therapy.

Vitamin B12 deficiency may suppress the signs of polycythemia vera. Treatment with vitamin B12 may unmask this condition.

If a patient is not properly maintained with Nascobal® Nasal Spray, intramuscular vitamin B12 is necessary for adequate treatment of the patient. No single regimen fits all cases, and the status of the patient observed in follow-up is the final criterion for adequacy of therapy.

The effectiveness of Nascobal Nasal Spray in patients with nasal congestion, allergic rhinitis and upper respiratory infections has not been determined. Therefore, treatment with Nascobal Nasal Spray should be deferred until symptoms have subsided.

2. INFORMATION FOR PATIENTS

Patients with pernicious anemia should be instructed that they will require weekly intranasal administration of Nascobal Nasal Spray for the remainder of their lives. Failure to do so will result in return of the anemia and in development of incapacitating and irreversible damage to the nerves of the spinal cord. Also, patients should be warned about the danger of taking folic acid in place of vitamin B12, because the former may prevent anemia but allow progression of subacute combined degeneration of the spinal cord.

(Hot foods may cause nasal secretions and a resulting loss of medication; therefore, patients should be told to administer Nascobal Nasal Spray at least one hour before or one hour after ingestion of hot foods or liquids.)

A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B12. Therefore, patients following such a diet should be advised to take Nascobal Nasal Spray weekly. The need for vitamin B12 is increased by pregnancy and lactation. Deficiency has been recognized in infants of vegetarian mothers who were breast fed, even though the mothers had no symptoms of deficiency at the time.

Because the nasal dosage forms of vitamin B12 have a lower absorption than intramuscular dosage, nasal dosage forms are administered weekly, rather than the monthly intramuscular dosage. As shown in the Figure above, at the end of a month, weekly nasal administration results in significantly higher serum vitamin B12 levels than after intramuscular administration. The patient should also understand the importance of returning for follow-up blood tests every 3 to 6 months to confirm adequacy of the therapy.

Careful instructions on the actuator assembly, removal of the safety clip, priming of the actuator and nasal administration of Nascobal Nasal Spray should be given to the patient. Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient.

3. LABORATORY TESTS

Hematocrit, reticulocyte count, vitamin B12, folate and iron levels should be obtained prior to treatment. If folate levels are low, folic acid should also be administered. All hematologic parameters should be normal when beginning treatment with Nascobal® Nasal Spray.

Vitamin B12 blood levels and peripheral blood counts must be monitored initially at one month after the start of treatment with Nascobal® Nasal Spray, and then at intervals of 3 to 6 months.

A decline in the serum levels of B12 after one month of treatment with B12 nasal spray may indicate that the dose may need to be adjusted upward. Patients should be seen one month after each dose adjustment; continued low levels of serum B12 may indicate that the patient is not a candidate for this mode of administration.

Patients with pernicious anemia have about 3 times the incidence of carcinoma of the stomach as in the general population, so appropriate tests for this condition should be carried out when indicated.

4. DRUG/LABORATORY TEST INTERACTIONS

Persons taking most antibiotics, methotrexate or pyrimethamine invalidate folic acid and vitamin B12 diagnostic blood assays.

Colchicine, para-aminosalicylic acid and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B12.

5. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term studies in animals to evaluate carcinogenic potential have not been done. There is no evidence from long-term use in patients with pernicious anemia that vitamin B12 is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this is believed to be related to the underlying pathology and not to treatment with vitamin B12.

6. PREGNANCY

Pregnancy Category C: Animal reproduction studies have not been conducted with vitamin B12. It is also not known whether vitamin B12 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adequate and well-controlled studies have not been done in pregnant women. However, vitamin B12 is an essential vitamin and requirements are increased during pregnancy. Amounts of vitamin B12 that are recommended by the Food and Nutrition Board, National Academy of Science - National Research Council for pregnant women should be consumed during pregnancy.

7. NURSING MOTHERS

Vitamin B12 appears in the milk of nursing mothers in concentrations which approximate the mother's vitamin B12 blood level. Amounts of vitamin B12 that are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for lactating women should be consumed during lactation.

8. PEDIATRIC USE

Intake in pediatric patients should be in the amount recommended by the Food and Nutrition Board, National Academy of Science-National Research Council.

Adverse Reactions

The incidence of adverse experiences described in the Table below are based on data from a short-term clinical trial in vitamin B12 deficient patients in hematologic remission receiving Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration (N=24) and intramuscular vitamin B12 (N=25). In the pharmacokinetic study comparing Nascobal Nasal Spray and Nascobal Nasal Gel, the incidence of adverse events was similar.

Table Adverse Experiences by Body System, Number of Patients and Number of Occurrences by Treatment Following Intramuscular and Intranasal Administration of Cyanocobalamin.

* There may be a possible relationship between these adverse experiences and the study drugs. These adverse experiences could have also been produced by the patient’s clinical state or other concomitant therapy. ± Sore throat, Common cold
		Number of Patients (Occurrences)
Body System	Adverse Experience	Vitamin B12Nasal Gel,500mcgN=24	IntramuscularVitamin B12, 100 mcgN=25
Body as a Whole	Asthenia	1 (1)	4 (4)
	Back Pain	0 (0)	1 (1)
	Generalized Pain	0 (0)	2 (3)
	Headache	1 (2)*	5 (11)
	Infection±	3 (4)	3 (3)
Cardiovascular System	Peripheral Vascular Disorder	0 (0)	1 (1)
Digestive System	Dyspepsia	0 (0)	1 (2)
	Glossitis	1 (1)	0 (0)
	Nausea	1 (1)*	1 (1)
	Nausea and Vomiting	0 (0)	1 (1)
	Vomiting	0 (0)	1 (1)
Musculoskeletal System	Arthritis	0 (0)	2 (2)
	Myalgia	0 (0)	1 (1)
Nervous System	Abnormal Gait	0 (0)	1 (1)
	Anxiety	0 (0)	1 (1)*
	Dizziness	0 (0)	3 (3)
	Hypoesthesia	0 (0)	1 (1)
	Incoordination	0 (0)	1 (2)*
	Nervousness	0 (0)	1 (3)*
	Paresthesia	1 (1)	1 (1)
Respiratory System	Dyspnea	0 (0)	1 (1)
	Rhinitis	1 (1)	2 (2)

The intensity of the reported adverse experiences following the administration of Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration and intramuscular vitamin B12 were generally mild. One patient reported severe headache following intramuscular dosing. Similarly, a few adverse experiences of moderate intensity were reported following intramuscular dosing (two headaches and rhinitis; one dyspepsia, arthritis, and dizziness), and dosing with Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration (one headache, infection, and paresthesia).

The majority of the reported adverse experiences following dosing with Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration and intramuscular vitamin B12 were judged to be intercurrent events. For the other reported adverse experiences, the relationship to study drug was judged as "possible" or "remote". Of the adverse experiences judged to be of "possible" relationship to the study drug, anxiety, incoordination, and nervousness were reported following intramuscular vitamin B12 and headache, nausea, and rhinitis were reported following dosing with Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration.

The following adverse reactions have been reported with parenteral vitamin B12:

Cardiovascular: Pulmonary edema and congestive heart failure early in treatment; peripheral vascular thrombosis.

Hematological: Polycythemia vera.

Gastrointestinal: Mild transient diarrhea.

Dermatological: Itching; transitory exanthema.

Miscellaneous: Feeling of swelling of the entire body.

Overdosage

No overdosage has been reported with Nascobal Nasal Spray, Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration or parenteral vitamin B12.

Nascobal Dosage and Administration

The recommended initial dose of Nascobal Nasal Spray is one spray (500 mcg) administered in ONE nostril once weekly. Nascobal Nasal Spray should be administered at least one hour before or one hour after ingestion of hot foods or liquids. Periodic monitoring of serum B12 levels should be obtained to establish adequacy of therapy.

Priming (Activation) of Pump

Before the first dose and administration, the pump must be primed. Remove the clear plastic safety clip from the pump. To prime the pump, place nozzle between the first and second finger with the thumb on the bottom of the bottle. Pump the unit firmly and quickly until the first appearance of spray. Then prime the pump an additional 2 times. Now the nasal spray is ready for use. The unit must be re-primed before each dose. Prime the pump once immediately before each administration of dose 2 through 4.

See LABORATORY TESTS for monitoring B12 levels and adjustment of dosage.

How is Nascobal Supplied

Nascobal Nasal Spray is available as a spray in 3 mL glass bottles containing 1.3 mL of solution. It is available in a dosage strength of 500 mcg per actuation (0.1 mL/actuation). A screw-on actuator is provided. This actuator, following priming, will deliver 0.1 mL of the spray. Nascobal Nasal Spray is provided in a carton containing a nasal spray actuator with dust cover, a bottle of nasal spray solution, and a package insert. One bottle will deliver 4 doses (NDC 49884-270-86).

PHARMACIST ASSEMBLY INSTRUCTIONS FOR Nascobal NASAL SPRAY

The pharmacist should assemble the Nascobal Nasal Spray unit prior to dispensing to the patient, according to the following instructions:

1. Open the carton and remove the spray actuator and spray solution bottle.


2. Assemble Nascobal Nasal Spray by first unscrewing the white cap from the spray solution bottle and screwing the actuator unit tightly onto the bottle. Make sure the clear dust cover is on the pump unit.


3. Return the Nascobal Nasal Spray bottle to the carton for dispensing to the patient.

INFORMATION FOR PATIENTS

Patients with pernicious anemia should be instructed that they will require weekly intranasal administration of Nascobal Nasal Spray for the remainder of their lives. Failure to do so will result in return of the anemia and in development of incapacitating and irreversible damage to the nerves of the spinal cord. Also, patients should be warned about the danger of taking folic acid in place of vitamin B12, because the former may prevent anemia but allow progression of subacute combined degeneration of the spinal cord.

(Hot foods may cause nasal secretions and a resulting loss of medication; therefore, patients should be told to administer Nascobal Nasal Spray at least one hour before or one hour after ingestion of hot foods or liquids.)

A vegetarian diet which contains no animal products (including milk products or eggs) does not supply any vitamin B12. Therefore, patients following such a diet should be advised to take Nascobal Nasal Spray weekly. The need for vitamin B12 is increased by pregnancy and lactation. Deficiency has been recognized in infants of vegetarian mothers who were breast fed, even though the mothers had no symptoms of deficiency at the time.

Because the nasal dosage forms of Vitamin B12 have a lower absorption than intramuscular dosage, nasal dosage forms are administered weekly, rather than the monthly intramuscular dosage. As shown in the Figure above, at the end of a month, weekly nasal administration results in significantly higher serum Vitamin B12 levels than after intramuscular administration. The patient should also understand the importance of returning for follow-up blood tests every 3 to 6 months to confirm adequacy of the therapy.

Careful instructions on the actuator assembly, removal of safety clip, priming of the actuator and nasal administration of Nascobal Nasal Spray should be given to the patient. Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient.

STORAGE CONDITIONS

Protect from light. Keep covered in carton until ready to use. Store upright at controlled room temperature 15°C to 30°C (59°F to 86°F). Protect from freezing.

To report suspected adverse reactions, contact Par Pharmaceutical Companies, Inc. at 1-800-828-9393.

Distributed by:

Par Pharmaceutical Companies, Inc

Spring Valley, NY 10977

OS270-01-03

Rev. 07/2011

FOR NASAL USE ONLY

KEEP OUT OF REACH OF CHILDREN

Each 0.1 mL contains 500mcg Cyancobalamin USP and the following inactive ingredients: Citric Acid USP, Sodium Citrate USP, Glycerin USP, Benzalkonium Chloride NF and Purified Water USP.

One bottle will deliver four doses.

Read instructions carefully before using.

See package insert for complete prescribing information.

Store upright at controlled room temperature 15°-30° C (59°-86° F).

PACKAGE LABEL-PRINICIPAL DISPLAY PANEL: Nascobal NASAL SPRAY 500MCG/SPRAY

NDC 49884-270-14

Nascobal® Nasal Spray

(Cyanocobalamin, USP)

500mcg/spray

2.3mL (8 sprays)

PACKAGE LABEL-PRINICIPAL DISPLAY PANEL: Nascobal NASAL SPRAY 500MCG/SPRAY

NDC 49884-270-86

Nascobal® Nasal Spray

(Cyanocobalamin, USP)

500mcg/spray

1.3mL (4 sprays)

Nascobal   cyanocobalamin  spray

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49884-270 Route of Administration NASAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CYANOCOBALAMIN (CYANOCOBALAMIN) CYANOCOBALAMIN 500 ug

Inactive Ingredients Ingredient Name Strength SODIUM CITRATE   CITRIC ACID   GLYCERIN   BENZALKONIUM CHLORIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 49884-270-86 4 SPRAY In 1 BOTTLE None 2 49884-270-14 8 SPRAY In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021642	08/13/2009

Labeler - Par Pharmaceutical , Inc (092733690)

Registrant - Par Pharmaceutical , Inc (092733690)

Establishment
Name	Address	ID/FEI	Operations
Par Pharmaceutical , Inc		092733690	manufacture

Revised: 08/2011Par Pharmaceutical , Inc

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