Levoglutil Vitaminado

Calcium Lactate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Levoglutil Vitaminado (Calcium Lactate) reviews

1 INDICATIONS AND USAGE

Levoglutil Vitaminado (Calcium Lactate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Levoglutil Vitaminado (Calcium Lactate) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Levoglutil Vitaminado (Calcium Lactate) acetate capsule.

- Capsule: 667 mg Levoglutil Vitaminado (Calcium Lactate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Levoglutil Vitaminado acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Levoglutil Vitaminado (Calcium Lactate) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Levoglutil Vitaminado (Calcium Lactate), including Levoglutil Vitaminado (Calcium Lactate) acetate. Avoid the use of Levoglutil Vitaminado (Calcium Lactate) supplements, including Levoglutil Vitaminado (Calcium Lactate) based nonprescription antacids, concurrently with Levoglutil Vitaminado (Calcium Lactate) acetate.

An overdose of Levoglutil Vitaminado (Calcium Lactate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Levoglutil Vitaminado (Calcium Lactate) levels twice weekly. Should hypercalcemia develop, reduce the Levoglutil Vitaminado (Calcium Lactate) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Levoglutil Vitaminado (Calcium Lactate) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Levoglutil Vitaminado (Calcium Lactate) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Levoglutil Vitaminado (Calcium Lactate) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Levoglutil Vitaminado (Calcium Lactate) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Levoglutil Vitaminado (Calcium Lactate) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Levoglutil Vitaminado (Calcium Lactate) acetate has been generally well tolerated.

Levoglutil Vitaminado (Calcium Lactate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Levoglutil Vitaminado (Calcium Lactate) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Levoglutil Vitaminado (Calcium Lactate) concentration could reduce the incidence and severity of Levoglutil Vitaminado (Calcium Lactate) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Levoglutil Vitaminado (Calcium Lactate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Levoglutil Vitaminado acetate is characterized by the potential of Levoglutil Vitaminado (Calcium Lactate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Levoglutil Vitaminado (Calcium Lactate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Levoglutil Vitaminado (Calcium Lactate) acetate and most concomitant drugs. When administering an oral medication with Levoglutil Vitaminado (Calcium Lactate) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Levoglutil Vitaminado (Calcium Lactate) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Levoglutil Vitaminado (Calcium Lactate) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Levoglutil Vitaminado (Calcium Lactate) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Levoglutil Vitaminado (Calcium Lactate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Levoglutil Vitaminado acetate capsules contains Levoglutil Vitaminado (Calcium Lactate) acetate. Animal reproduction studies have not been conducted with Levoglutil Vitaminado (Calcium Lactate) acetate, and there are no adequate and well controlled studies of Levoglutil Vitaminado (Calcium Lactate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Levoglutil Vitaminado (Calcium Lactate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Levoglutil Vitaminado (Calcium Lactate) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Levoglutil Vitaminado (Calcium Lactate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Levoglutil Vitaminado (Calcium Lactate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Levoglutil Vitaminado (Calcium Lactate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Levoglutil Vitaminado Acetate Capsules contains Levoglutil Vitaminado (Calcium Lactate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Levoglutil Vitaminado (Calcium Lactate) acetate is not expected to harm an infant, provided maternal serum Levoglutil Vitaminado (Calcium Lactate) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Levoglutil Vitaminado (Calcium Lactate) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Levoglutil Vitaminado (Calcium Lactate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Levoglutil Vitaminado (Calcium Lactate) acetate acts as a phosphate binder. Its chemical name is Levoglutil Vitaminado (Calcium Lactate) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Levoglutil Vitaminado (Calcium Lactate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Levoglutil Vitaminado (Calcium Lactate), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Levoglutil Vitaminado (Calcium Lactate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Levoglutil Vitaminado resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Levoglutil Vitaminado (Calcium Lactate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Levoglutil Vitaminado (Calcium Lactate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Levoglutil Vitaminado (Calcium Lactate) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Levoglutil Vitaminado (Calcium Lactate) acetate.

14 CLINICAL STUDIES

Effectiveness of Levoglutil Vitaminado (Calcium Lactate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Levoglutil Vitaminado (Calcium Lactate) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Levoglutil Vitaminado (Calcium Lactate) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Levoglutil Vitaminado (Calcium Lactate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Levoglutil Vitaminado (Calcium Lactate) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Levoglutil Vitaminado (Calcium Lactate) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Levoglutil Vitaminado (Calcium Lactate) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Levoglutil Vitaminado (Calcium Lactate) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Levoglutil Vitaminado (Calcium Lactate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Levoglutil Vitaminado (Calcium Lactate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Levoglutil Vitaminado (Calcium Lactate) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Levoglutil Vitaminado (Calcium Lactate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Levoglutil Vitaminado (Calcium Lactate) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Levoglutil Vitaminado (Calcium Lactate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Glutamine:

• Indication and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Levoglutil Vitaminado (Glutamine) reviews

1 INDICATION AND USAGE

Levoglutil Vitaminado (Glutamine)^® [L-glutamine powder for oral solution] is indicated for the treatment of Short Bowel Syndrome (SBS) in patients receiving specialized nutritional support when used in conjunction with a recombinant human growth hormone that is approved for this indication [see Dosage and Administration (2) ].

Levoglutil Vitaminado (Glutamine) and recombinant human growth hormone (rhGH) therapy should be used in conjunction with optimal management of SBS. Optimal management of SBS may include a specialized oral diet, enteral feedings, parenteral nutrition, fluid and micronutrient supplements. A specialized oral diet may consist of a high carbohydrate, low-fat diet, adjusted for individual patient requirements and preferences.

Routine monitoring of renal and hepatic function is recommended in patients receiving Levoglutil Vitaminado (Glutamine) and intravenous parenteral nutrition (IPN), particularly in those with renal or hepatic impairment. Levoglutil Vitaminado (Glutamine) is metabolized to glutamate and ammonia, which may increase in patients with hepatic dysfunction.

The safety and efficacy of Levoglutil Vitaminado (Glutamine) have not been studied beyond 16 weeks of treatment.

NutreStore® is an amino acid indicated for:

• the treatment of Short Bowel Syndrome in patients receiving specialized nutritional support when used in conjunction with a recombinant human growth hormone that is approved for this indication (1)

2 DOSAGE AND ADMINISTRATION

Levoglutil Vitaminado (Glutamine) should be administered as a cotherapy with rhGH ] for injection) followed by continued Levoglutil Vitaminado (Glutamine) for up to 16 weeks.

The recommended dosage of Levoglutil Vitaminado (Glutamine) is 30 g daily in divided doses (5 g taken 6 times each day orally) for up to 16 weeks. Each dose of Levoglutil Vitaminado (Glutamine) (5 g) should be reconstituted in 8-oz (250-mL) of water prior to consumption.

Levoglutil Vitaminado (Glutamine) should be taken with meals or snacks at 2- to 3-hour intervals while awake. The volume of water may be varied according to the patient's preference. In the event of a patient's transient intolerance to oral intake, a dose may be delayed for up to 2 hours.

• 30 g daily in divided doses (5 g taken 6 times each day orally) for up to 16 weeks (2)
• Each dose should be reconstituted in 8 oz (250 mL) of water prior to consumption (2)
• Should be taken with meals or snacks at 2- to 3-hour interval while awake (2)

3 DOSAGE FORMS AND STRENGTHS

Levoglutil Vitaminado (Glutamine) is supplied in preprinted paper-foil-plastic laminate packets containing 5 g of L-glutamine powder.

• Pre-printed paper-foil-plastic laminate packets: 5 g powder (3)

4 CONTRAINDICATIONS

None.

• None (4)

5 WARNINGS AND PRECAUTIONS

• Routine monitoring of renal and hepatic function is recommended in patients receiving lPN, particularly in those with renal or hepatic impairment

5.1 Increased Serum Ammonia and Glutamate

Levoglutil Vitaminado (Glutamine) is metabolized to glutamate and ammonia, which may increase in patients with hepatic dysfunction. Therefore, routine monitoring of renal and hepatic function is recommended in patients receiving intravenous parenteral nutrition (IPN) and Levoglutil Vitaminado (Glutamine), particularly in those with renal or hepatic impairment.

6 ADVERSE REACTIONS

Most common adverse reactions are :

• In initial four (4) weeks (incidence >10%): flatulence, abdominal pain, nausea, tenesmus, vomiting, hemorrhoids, mouth dry.
• In weeks 5-18 (incidence >10%): nausea, vomiting, tenesmus, pancreatitis, constipation, Crohn's disease aggravated, gastric ulcer, gastrointestinal fistula.

To report SUSPECTED ADVERSE REACTIONS, contact Emmaus Medical, Inc. at 1-877-420-6493 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice

Table 1 provides the number of subjects by system-organ class experiencing at least one adverse reaction during the 4-week treatment period of the SBS study. To be listed in Table 1, an adverse reaction must have occurred in more than 10% of subjects in any treatment group.

Table 2 summarizes the number of subjects by system-organ class who experienced an AR during weeks 5 to 18 of the randomized, controlled SBS study. To be listed in Table 2, an AR must have occurred in more than 10% of subjects in any treatment group.

During the initial 4-week treatment period, 100% of patients receiving growth hormone with and without Levoglutil Vitaminado (Glutamine) reported at least one AR, whereas 89% of patients receiving growth hormone placebo with Levoglutil Vitaminado (Glutamine) reported at least one AR. During weeks 5 to 18, 81% of patients receiving growth hormone with Levoglutil Vitaminado (Glutamine), 80% of patients receiving growth hormone without Levoglutil Vitaminado (Glutamine) and 78% of patients receiving growth hormone placebo with Levoglutil Vitaminado (Glutamine) experienced at least one AR. There were no deaths in this study.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with Levoglutil Vitaminado. It is also not known whether Levoglutil Vitaminado (Glutamine) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Levoglutil Vitaminado (Glutamine) should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery

The effect of L-glutamine on labor and delivery is unknown.

8.3 Nursing Mothers

It is not known whether L-glutamine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when L-glutamine is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of L-glutamine in pediatric patients have not been established.

8.5 Geriatric Use

The clinical trial enrolled SBS patients between the ages of ZO and 75 years. Only 8 of the 41 subjects evaluated were ≥65 years of age. The clinical trial of oral Levoglutil Vitaminado did not include sufficient numbers of subjects aged 65 years and over to determine if they respond differently than younger subjects. In general, dose selection for an elderly patient should be individualized, because of the greater frequency of decreased hepatic, renal, or cardiac function, as well as concomitant disease in this population.

8.6 Hepatic Impairment

Levoglutil Vitaminado (Glutamine) is metabolized to glutamate and ammonia, which may increase in patients with hepatic dysfunction. Therefore, routine monitoring of hepatic function is recommended in patients receiving intravenous parental nutrition (IPN) and Levoglutil Vitaminado (Glutamine).

8.7 Renal Impairment

Levoglutil Vitaminado (Glutamine) is metabolized to glutamate and ammonia. Routine monitoring of renal function is recommended in patients receiving intravenous parental nutrition (IPN) and Levoglutil Vitaminado (Glutamine).

10 OVERDOSAGE

Single oral doses of Levoglutil Vitaminado (Glutamine) at about 20 to 22 g/kg, 8 to 11 g/kg, and 19 g/kg were lethal in mice, rats, and rabbits, respectively.

11 DESCRIPTION

Levoglutil Vitaminado (Glutamine) (L-glutamine powder for oral solution) for oral administration is formulated as a white crystalline powder in a paper-foil-plastic laminate packet. Each packet of Levoglutil Vitaminado (Glutamine) contains 5 g of L-glutamine. The amino acid Levoglutil Vitaminado (Glutamine) is also known as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, (S)-2,5-diamino-5-oxopentanoic acid, or L-glutamine. The molecular formula of Levoglutil Vitaminado (Glutamine) is C₅H₁₀N₂O₃, and the molecular weight is 146.15 d. Levoglutil Vitaminado (Glutamine) has the following structural formula:

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

L-glutamine has important functions in regulation of gastrointestinal cell growth, function, and regeneration. Under normal conditions, Levoglutil Vitaminado concentration is maintained in the body by dietary intake and synthesis from endogenous glutamate. Data from clinical studies indicate that the role of and nutritional requirements for Levoglutil Vitaminado (Glutamine) during catabolic illness, trauma, and infection may differ significantly from the role of and nutritional requirements for Levoglutil Vitaminado (Glutamine) in healthy individuals. Levoglutil Vitaminado (Glutamine) concentrations decrease and tissue Levoglutil Vitaminado (Glutamine) metabolism increases during many catabolic disease states, and thus Levoglutil Vitaminado (Glutamine) is often considered a "conditionally essential" amino acid.

12.2 Pharmacodynamics

When Levoglutil Vitaminado (Glutamine) was administered in combination with rhGH to rats, villous height, bowel growth, plasma insulin-like growth factor I, and body weight were significantly higher than in rats treated with either Levoglutil Vitaminado (Glutamine) or rhGH alone.

12.3 Pharmacokinetics

The pharmacokinetics of L-glutamine as described below are based on literature data in healthy subjects. The pharmacokinetics in patients with SBS have not been determined. The plasma Levoglutil Vitaminado (Glutamine) concentrations in these patients following oral administration are expected to be highly variable depending on the length, segment, and presence/ absence of ileal-cecal valve for the remnant bowel.

Absorption

Following single dose oral administration of Levoglutil Vitaminado (Glutamine) at 0.1 g/kg to six subjects, mean peak blood Levoglutil Vitaminado (Glutamine) concentration was 1028 µM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses have not been adequately characterized.

Distribution

After an intravenous bolus dose in three subjects, the volume of distribution was estimated to be approximately 200 mL/kg.

Metabolism

Endogenous Levoglutil Vitaminado (Glutamine) participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous Levoglutil Vitaminado (Glutamine) is anticipated to undergo similar metabolism.

Elimination

Metabolism is the major route of elimination for Levoglutil Vitaminado (Glutamine). Although Levoglutil Vitaminado (Glutamine) is eliminated by glomerular filtration, it is almost completely reabsorbed by the renal tubules. After an IV bolus dose in three subjects, the terminal half-life of Levoglutil Vitaminado (Glutamine) was approximately 1 hour.

Specific Populations

There are no studies to determine the effect of race, age, or gender on the pharmacokinetics of L-glutamine.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted. Because metabolism of Levoglutil Vitaminado (Glutamine) is mediated via non-CYP enzymes, Levoglutil Vitaminado (Glutamine) pharmacokinetics are unlikely to be affected by other agents through CYP enzyme inhibition or induction.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine. Studies to evaluate its potential for impairment of fertility or its mutagenic potential have not been conducted.

14 CLINICAL STUDIES

14.1 Short Bowel Syndrome

A randomized, controlled, 3-arm, double-blind, parallel-group clinical study evaluated the efficacy and safety of oral Levoglutil Vitaminado (Glutamine) as a cotherapy with rhGH in subjects with SBS who were dependent on intravenous parenteral nutrition (IPN) for nutritional support. The primary endpoint was the change in weekly total IPN volume defined as the sum of the volumes of lPN, supplemental lipid emulsion (SLE), and intravenous hydration fluid. The secondary endpoints were the change in weekly IPN caloric content and the change in the frequency of IPN administration per week.

All subjects received a specialized oral diet (SOD) for the duration of the study. Following a two-week equilibration period, treatment was administered in a double blind manner. Group A (N=16) received rhGH for four weeks plus oral Levoglutil Vitaminado (Glutamine) placebo for 16 weeks, Group B (N=16) received rhGH for four weeks plus oral Levoglutil Vitaminado (Glutamine) for 16 weeks, and Group C (N=9), received rhGH placebo for four weeks plus oral Levoglutil Vitaminado (Glutamine) for 16 weeks. The efficacy of Levoglutil Vitaminado (Glutamine) was assessed by comparing the cotherapy (rhGH and oral Levoglutil Vitaminado (Glutamine)) to rhGH alone.

After 4 weeks of treatment with subcutaneous rhGH (0.1 mg/kg/d) and oral Levoglutil Vitaminado (Glutamine) (30 g/ d) (Group B), subjects with SBS reduced their requirement for IPN volume (-7.7 L/wk), IPN caloric content (-5751 kcal/wk), and weekly frequency of IPN administration (-4.2 d/wk).

IPN volume requirements were Significantly reduced in subjects receiving subcutaneous rhGH and oral Levoglutil Vitaminado (Glutamine) (Group B) when compared with IPN volume requirements in subjects receiving either treatment alone.

The change in weekly IPN volume, calories and frequency was assessed from Week 2 to Week 18. The data support that the treatment effect is maintained for 16 weeks. The efficacy of oral Levoglutil Vitaminado (Glutamine) beyond 16 weeks of treatment has not been adequately studied.

16 HOW SUPPLIED/STORAGE AND HANDLING

Levoglutil Vitaminado (Glutamine) is supplied in preprinted paper-foil-plastic laminate packets containing 5 g of L-glutamine powder and is supplied as follows:

• Carton of 84 packets (NDC 42457-001-84)

Store at 25°C (77°F) with excursions allowed to 15°-30°C (59°-86°F).

17 PATIENT COUNSELING INFORMATION

17.1 Dosing Instructions

Levoglutil Vitaminado (Glutamine) should be taken with meals or snacks at 2- to 3-hour intervals while awake. The volume of water may be varied according to the patient's preference. In the event of a patient's transient intolerance to oral intake, a dose may be delayed for up to 2 hours.

For additional information concerning Levoglutil Vitaminado (Glutamine), contact:

Manufactured for:

Emmaus

MEDICAL, INC.

20725 S. Western Ave., Suite 136

Torrance, CA 90501-1884

Tel: 1-877-420-6493

www.nutrestore.com

© 2013 Emmaus Medical, Inc.

FDA-Approved Patient Labeling

Patient Information

Levoglutil Vitaminado (Glutamine)^® (NOO-tre-stor)

[L-glutamine powder for oral solution] (GLOO-tah-min)

Please read this leaflet carefully before you start to use Levoglutil Vitaminado (Glutamine)^® and each time your prescription is refilled since there may be new information. The information in this leaflet does not take the place of regularly talking with your doctor or health care professional.

What is Levoglutil Vitaminado (Glutamine)^®?

Levoglutil Vitaminado (Glutamine)^® is the amino acid L-glutamine, identical to the L-glutamine that your body produces. Levoglutil Vitaminado (Glutamine)^® is used together with a human growth hormone, approved for treating short bowel syndrome [SBS], in patients receiving a specialized diet tailored to meet their individual needs.

Why has my doctor prescribed Levoglutil Vitaminado (Glutamine)^®?

Your doctor prescribed Levoglutil Vitaminado (Glutamine)^® initially in combination with human growth hormone to help decrease your need for intravenous feedings. After treatment in combination with human growth hormone, you will continue to take Levoglutil Vitaminado (Glutamine)^® alone to maintain the treatment effect. During your treatment with Levoglutil Vitaminado (Glutamine)^® you will be taking up to 6 packets of Levoglutil Vitaminado (Glutamine)^® a day. You will also receive instructions from your doctor or a dietitian on the proper diet you should follow during this treatment period as well as after your treatment is over. Please refer to the patient package leaflet available for human growth hormone for more information on how to take human growth hormone.

What should I tell my doctor before taking Levoglutil Vitaminado (Glutamine)^®?

Tell your doctor about all of your conditions including if you:

• are pregnant or planning to become pregnant. It is not known if NutreStore® can harm your unborn baby.
• are breast feeding. It is not known if Levoglutil Vitaminado (Glutamine)^® passes into your milk and if it can harm your baby. You should talk to your doctor about breastfeeding while taking Levoglutil Vitaminado (Glutamine)^®.
• have liver or kidney problems. Your doctor may do blood tests to check your liver and kidney function while you are taking Levoglutil Vitaminado (Glutamine)^®.
• are older than 65 years of age. Your dose of Levoglutil Vitaminado (Glutamine)^® may need to be adjusted.

Tell your doctor about all the medicines you take including prescription medicines, non-prescription medicines, vitamins, or herbal supplements. It is not known if Levoglutil Vitaminado (Glutamine)^® and other medicines can affect each other.

What should I avoid while taking Levoglutil Vitaminado (Glutamine)^®?

• Pregnancy. You should talk to your doctor if you are planning to become pregnant while taking Levoglutil Vitaminado (Glutamine)^®. It is not known whether Levoglutil Vitaminado (Glutamine)^® can affect the ability of a woman to become pregnant. It is also not known whether Levoglutil Vitaminado (Glutamine)^® can cause harm to a fetus when taken by a pregnant woman or if Levoglutil Vitaminado (Glutamine)^® has an effect on labor and delivery.
• Breastfeeding. You should talk to your doctor before breastfeeding an infant while taking Levoglutil Vitaminado (Glutamine)^®. It is not known whether the Levoglutil Vitaminado (Glutamine) in Levoglutil Vitaminado (Glutamine)^® can be passed to an infant in mother's milk, and it is not clear whether the drug could harm the infant if it is passed in mother's milk.

What are the possible side effects of Levoglutil Vitaminado (Glutamine)^®?

Many patients taking Levoglutil Vitaminado (Glutamine)^® and human growth hormone for the treatment of SBS experience side effects.

Whether or not you experience side effects, you and your doctor should periodically talk about your general health.

• Your doctor may want to monitor you more closely and ask you to have blood tests done more frequently.

Digestive system.

The possible side effects you may experience while taking Levoglutil Vitaminado (Glutamine)^® include vomiting, hemorrhoids, pancreatitis, aggravation of Crohn's disease, gastric ulcer, and gastrointestinal fistula (opening between stomach and intestine).

The possible related symptoms you may experience while taking Levoglutil Vitaminado (Glutamine)^® include urge to empty bowel, gas, abdominal pain, nausea, dry mouth and constipation.

These side effects and related symptoms may be similar to those you have experienced while being treated for SBS. You should talk to your doctor about these problems before starting an over-the-counter medication to treat these symptoms. It is important for you to follow your doctor's or dietitian's instructions on the type of diet best for you.

Please refer also to the patient package leaflet available for human growth hormone for more information on the possible benefits and side effects of human growth hormone.

Tell your doctor about any side effects that bother you or that do not go away.

These are not all the side effects with Levoglutil Vitaminado (Glutamine)^®. For more information, ask your doctor or pharmacist.

How should I take Levoglutil Vitaminado (Glutamine)^®?

Levoglutil Vitaminado (Glutamine)^® should be taken up to 6 times a day (every 2 to 3 hours during the day) with a meal or snack. This should be continued every day for as long as your doctor prescribes. Each dose of Levoglutil Vitaminado (Glutamine)^® should be prepared by pouring the contents of one packet into an 8-oz glass of water and stirring for approximately 1 minute. After stirring, you should drink the Levoglutil Vitaminado (Glutamine)^® within 2 hours. If you miss a dose, you should take your next dose as soon as you remember or are able to take it. Do not take more than 6 packets each day.

What kind of food should I eat during my treatment with Levoglutil Vitaminado (Glutamine)^®?

Your doctor or dietitian will prescribe for you the types and quantities of foods you should eat during your treatment with Levoglutil Vitaminado (Glutamine)^®. These foods are not special and can be purchased from your local market. Your likes and dislikes should be taken into consideration when your meal plan is created.

Your doctor or dietitian will advise you on how many times a day you should eat. Your doctor or dietitian will adjust your diet as needed during your treatment with Levoglutil Vitaminado (Glutamine)^®. It is important that you carefully follow the eating plan your doctor or dietitian gives you.

Storage conditions for Levoglutil Vitaminado (Glutamine)^®

Packets of Levoglutil Vitaminado (Glutamine)^® should be stored at room temperature (25°C / 77°F). Expiration dates are stated on product labels. Do not use any damaged packets of Levoglutil Vitaminado (Glutamine)^®. Keep Levoglutil Vitaminado (Glutamine)^® and all medicines out of the reach of children.

General information about prescription medicines

This medication has been prescribed for a particular medical condition. Do not use it for another condition or give this drug to anyone else. If you have any questions, you should speak with your doctor or health care professional. You may also ask your doctor or pharmacist for a copy of the information provided to them with the product. Keep this and all drugs out of the reach of children.

For additional information, you may call the Levoglutil Vitaminado (Glutamine)^® patient hotline at 1-877-420-6493.

PRINCIPAL DISPLAY PANEL - 84 Packet Carton

Levoglutil Vitaminado (Glutamine)^®

[L-glutamine powder for oral solution]

Principal Display Panel - 84 Packet Carton

Magnesium Gluconate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Levoglutil Vitaminado (Magnesium Gluconate) reviews

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP is a sterile solution of Levoglutil Vitaminado (Magnesium Gluconate) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Levoglutil Vitaminado (Magnesium Gluconate) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Levoglutil Vitaminado (Magnesium Gluconate) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Levoglutil Vitaminado (Magnesium Gluconate). While there are large stores of Levoglutil Vitaminado (Magnesium Gluconate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Levoglutil Vitaminado (Magnesium Gluconate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Levoglutil Vitaminado (Magnesium Gluconate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Levoglutil Vitaminado (Magnesium Gluconate) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Levoglutil Vitaminado (Magnesium Gluconate) levels range from 1.5 to 2.5 mEq/liter.

As plasma Levoglutil Vitaminado (Magnesium Gluconate) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Levoglutil Vitaminado (Magnesium Gluconate). Serum Levoglutil Vitaminado (Magnesium Gluconate) concentrations in excess of 12 mEq/L may be fatal.

Levoglutil Vitaminado (Magnesium Gluconate) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Levoglutil Vitaminado (Magnesium Gluconate) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Levoglutil Vitaminado (Magnesium Gluconate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP is suitable for replacement therapy in Levoglutil Vitaminado (Magnesium Gluconate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Levoglutil Vitaminado (Magnesium Gluconate) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Levoglutil Vitaminado (Magnesium Gluconate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Levoglutil Vitaminado (Magnesium Gluconate) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Levoglutil Vitaminado (Magnesium Gluconate) sulfate should be used during pregnancy only if clearly needed. If Levoglutil Vitaminado (Magnesium Gluconate) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Levoglutil Vitaminado (Magnesium Gluconate) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Levoglutil Vitaminado (Magnesium Gluconate) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Levoglutil Vitaminado (Magnesium Gluconate), their dosage should be adjusted with caution because of additive CNS depressant effects of Levoglutil Vitaminado (Magnesium Gluconate).

Because Levoglutil Vitaminado (Magnesium Gluconate) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Levoglutil Vitaminado (Magnesium Gluconate) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Levoglutil Vitaminado (Magnesium Gluconate) should be given until they return. Serum Levoglutil Vitaminado (Magnesium Gluconate) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Levoglutil Vitaminado (Magnesium Gluconate) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Levoglutil Vitaminado (Magnesium Gluconate) intoxication in eclampsia.

50% Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Levoglutil Vitaminado (Magnesium Gluconate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Levoglutil Vitaminado (Magnesium Gluconate) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Levoglutil Vitaminado (Magnesium Gluconate), their dosage should be adjusted with caution because of additive CNS depressant effects of Levoglutil Vitaminado (Magnesium Gluconate). CNS depression and peripheral transmission defects produced by Levoglutil Vitaminado (Magnesium Gluconate) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Levoglutil Vitaminado (Magnesium Gluconate) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Levoglutil Vitaminado (Magnesium Gluconate) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Levoglutil Vitaminado (Magnesium Gluconate) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Levoglutil Vitaminado (Magnesium Gluconate) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Levoglutil Vitaminado (Magnesium Gluconate) sulfate for more than 5 to 7 days.^1-10 Levoglutil Vitaminado (Magnesium Gluconate) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Levoglutil Vitaminado (Magnesium Gluconate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Levoglutil Vitaminado (Magnesium Gluconate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Levoglutil Vitaminado (Magnesium Gluconate) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Levoglutil Vitaminado (Magnesium Gluconate) is distributed into milk during parenteral Levoglutil Vitaminado (Magnesium Gluconate) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Levoglutil Vitaminado (Magnesium Gluconate) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Levoglutil Vitaminado (Magnesium Gluconate) usually are the result of Levoglutil Vitaminado (Magnesium Gluconate) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Levoglutil Vitaminado (Magnesium Gluconate) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Levoglutil Vitaminado (Magnesium Gluconate) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Levoglutil Vitaminado (Magnesium Gluconate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Levoglutil Vitaminado (Magnesium Gluconate).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Levoglutil Vitaminado (Magnesium Gluconate) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Levoglutil Vitaminado (Magnesium Gluconate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Levoglutil Vitaminado (Magnesium Gluconate) Deficiency

In the treatment of mild Levoglutil Vitaminado (Magnesium Gluconate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Levoglutil Vitaminado (Magnesium Gluconate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Levoglutil Vitaminado (Magnesium Gluconate) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Levoglutil Vitaminado (Magnesium Gluconate) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Levoglutil Vitaminado (Magnesium Gluconate) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Levoglutil Vitaminado (Magnesium Gluconate) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Levoglutil Vitaminado (Magnesium Gluconate) sulfate is 20 grams/48 hours and frequent serum Levoglutil Vitaminado (Magnesium Gluconate) concentrations must be obtained. Continuous use of Levoglutil Vitaminado (Magnesium Gluconate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Levoglutil Vitaminado (Magnesium Gluconate) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Levoglutil Vitaminado (Magnesium Gluconate) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Levoglutil Vitaminado (Magnesium Gluconate) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Levoglutil Vitaminado (Magnesium Gluconate) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP is supplied in single-dose containers as follows:

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Levoglutil Vitaminado (Magnesium Gluconate) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Levoglutil Vitaminado (Magnesium Gluconate) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Levoglutil Vitaminado (Magnesium Gluconate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Levoglutil Vitaminado (Magnesium Gluconate) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Levoglutil Vitaminado (Magnesium Gluconate) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Levoglutil Vitaminado (Magnesium Gluconate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Levoglutil Vitaminado (Magnesium Gluconate) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Levoglutil Vitaminado (Magnesium Gluconate) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Levoglutil Vitaminado (Magnesium Gluconate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Levoglutil Vitaminado (Magnesium Gluconate) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Levoglutil Vitaminado (Magnesium Gluconate) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Levoglutil Vitaminado (Magnesium Gluconate) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Levoglutil Vitaminado (Magnesium Gluconate) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Vitamin B12:

• Pharmacological action
• Pharmacokinetics
• Why is Levoglutil Vitaminado prescribed?
• Dosage and administration
• Levoglutil Vitaminado (Vitamin B12) side effects, adverse reactions
• Levoglutil Vitaminado contraindications
• Levoglutil Vitaminado using during pregnancy and breastfeeding
• Special instructions
• Levoglutil Vitaminado (Vitamin B12) drug interactions
• Levoglutil Vitaminado (Vitamin B12) reviews

Pharmacological action

Levoglutil Vitaminado refers to a group of water-soluble vitamins. It has high biological activity. Levoglutil Vitaminado (Vitamin B12) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Levoglutil Vitaminado (Vitamin B12) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Levoglutil Vitaminado prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Levoglutil Vitaminado (Vitamin B12) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Levoglutil Vitaminado is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Levoglutil Vitaminado (Vitamin B12) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Levoglutil Vitaminado (Vitamin B12) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Levoglutil Vitaminado (Vitamin B12) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Levoglutil Vitaminado (Vitamin B12) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Levoglutil Vitaminado contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Levoglutil Vitaminado using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Levoglutil Vitaminado 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Levoglutil Vitaminado (Vitamin B12) drug interactions

In an application of Levoglutil Vitaminado (Vitamin B12) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Levoglutil Vitaminado (Vitamin B12) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.