SG-Glutergen

Cholic Acid:

• 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
• SG-Glutergen (Cholic Acid) reviews

1 INDICATIONS AND USAGE

SG-Glutergen is a bile acid indicated for:

• Treatment of bile acid synthesis disorders due to single enzyme defects (SEDs). (1.1)
• Adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption (1.2)

Limitation of use:

The safety and effectiveness of SG-Glutergen (Cholic Acid) on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established. (1.3).

1.1 Bile Acid Synthesis Disorders due to Single Enzyme Defects

SG-Glutergen (Cholic Acid) is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SEDs) .

1.2 Peroxisomal Disorders Including Zellweger Spectrum Disorders

SG-Glutergen is indicated for adjunctive treatment of peroxisomal disorders (PDs) including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption .

1.3 Limitation of Use

The safety and effectiveness of SG-Glutergen (Cholic Acid) on extrahepatic manifestations of bile acid synthesis disorders due to SEDs or PDs including Zellweger spectrum disorders have not been established.

2 DOSAGE AND ADMINISTRATION

• The recommended dosage is 10 to 15 mg/kg once daily or in two divided doses, in pediatric patients and adults. See prescribing information for weight-based dosing tables.
• The recommended dosage in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg once daily or in two divided doses and is adjusted based on clinical response (2.1)
• Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next three years and annually thereafter. Administer the lowest dose that effectively maintains liver function (2.2)
• Discontinue SG-Glutergen (Cholic Acid) if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting a lower dose when parameters return to baseline. (2.2, 5.1, 8.6)

Administration Instructions:

• Take with food. (2.3)
• Do not crush or chew the capsules. For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with drink/food (2.3)

2.1 Dosage Regimen for Bile Acid Synthesis Disorders due to Single Enzyme Defects and Peroxisomal Disorders including Zellweger Spectrum Disorders

The recommended dosage of SG-Glutergen (Cholic Acid) is 10 to 15 mg/kg administered orally once daily, or in two divided doses, in pediatric patients and in adults.

Tables 1 and 2 show the number of capsules that should be administered daily to approximate a 10 mg/kg/day and 15 mg/kg/day dosage, respectively, using the available 50 mg and 250 mg capsules alone or in combination.

	10 mg/kg/day Dosage
Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
4 to 6	1	0
7 to 10	2	0
11 to 15	3	0
16 to 20	4	0
21 to 25	0	1
26 to 30	1	1
31 to 35	2	1
36 to 40	3	1
41 to 45	4	1
46 to 50	0	2
51 to 55	1	2
56 to 60	2	2
61 to 65	3	2
66 to 70	4	2
71 to 75	0	3
76 to 80	1	3

	15 mg/kg/day Dosage
Body Weight (kg)	Number of 50 mg capsules	Number of 250 mg capsules
4 to 5	1	0
6 to 9	2	0
10 to 13	3	0
14 to 16	4	0
17 to 19	0	1
20 to 23	1	1
24 to 26	2	1
27 to 29	3	1
30 to 33	4	1
34 to 36	0	2
37 to 39	1	2
40 to 43	2	2
44 to 46	3	2
47 to 49	4	2
50 to 53	0	3
54 to 56	1	3
57 to 59	2	3
60 to 63	3	3
64 to 66	4	3
67 to 69	0	4
70 to 73	1	4
74 to 76	2	4
77 to 79	3	4
80	4	4

Patients with newly diagnosed, or a family history of, familial hypertriglyceridemia may have poor absorption of SG-Glutergen (Cholic Acid) from the intestine and require a 10% increase in the recommended dosage to account for losses due to malabsorption. The recommended dosage of SG-Glutergen (Cholic Acid) in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg orally once daily, or in two divided doses. Adequacy of the dosage regimen can be determined by monitoring of patients' clinical response including steatorrhea, and laboratory values including transaminases, bilirubin and PT/INR.

2.2 Treatment Monitoring

Treatment with SG-Glutergen should be initiated and monitored by an experienced hepatologist or pediatric gastroenterologist.

Monitor serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the subsequent three years and annually thereafter. Monitor more frequently during periods of rapid growth, concomitant disease, and pregnancy. Administer the lowest dose of SG-Glutergen (Cholic Acid) that effectively maintains liver function .

Discontinue treatment with SG-Glutergen (Cholic Acid) if liver function does not improve within 3 months of the start of treatment or complete biliary obstruction develops.

Discontinue treatment with SG-Glutergen (Cholic Acid) at any time if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis . Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate SG-Glutergen (Cholic Acid) overdose [see Overdosage (10)]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

Assessment of serum or urinary bile acid levels using mass spectrometry is used in the diagnosis of bile acid synthesis disorders due to SEDs and PDs including Zellweger spectrum disorders. The utility of bile acid measurements in monitoring the clinical course of patients and in decisions regarding dose adjustment has not been demonstrated.

2.3 Administration Instructions

• Take SG-Glutergen (Cholic Acid) with food.
• Take SG-Glutergen (Cholic Acid) at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacid.
• Do not crush or chew the capsules.
• For patients unable to swallow the capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste:
  • Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food.
  • Mix the entire capsule contents with one or two tablespoons (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree.
  • Stir for 30 seconds.
  • The capsule contents will remain as fine granules in the milk or food, and will not dissolve.
  • Administer the mixture immediately

3 DOSAGE FORMS AND STRENGTHS

SG-Glutergen (Cholic Acid) is available in two capsule strengths.

• 50 mg capsule: Size number 2 Swedish orange capsule with cap imprinted with "50mg" and body imprinted with "ASK001". The capsules contain a white to off-white powder.
• 250 mg capsule: Size number 0 white capsule with a cap imprinted with "250mg" and body imprinted with "ASK002". The capsules contain a white to off-white powder.

Capsules: 50 mg, 250 mg (3)

4 CONTRAINDICATIONS

None.

None (4)

5 WARNINGS AND PRECAUTIONS

Exacerbation of Liver Impairment: Monitor liver function and discontinue SG-Glutergen if liver function worsens while on treatment (5.1)

5.1 Exacerbation of Liver Impairment

Monitor liver function and discontinue SG-Glutergen (Cholic Acid) in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) may indicate SG-Glutergen (Cholic Acid) overdose. . Discontinue treatment with SG-Glutergen (Cholic Acid) at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis.

Evidence of liver impairment was present before treatment with SG-Glutergen (Cholic Acid) in approximately 86% (44/51) of patients with bile acid synthesis disorders due to SEDs and in approximately 50% (14/28) of patients with PDs including Zellweger spectrum disorders. Five of the patients (3 SED and 2 PD) with liver impairment at baseline experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy following treatment. An additional 5 patients (2 SED and 3 PD) who did not have baseline cholestasis experienced an exacerbation of their liver disease while on treatment. Exacerbation of liver impairment by SG-Glutergen (Cholic Acid) in these patients cannot be ruled out.

Six patients with single enzyme defects underwent liver transplant, including four patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency.

6 ADVERSE REACTIONS

Most common adverse reactions are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Manchester Pharmaceuticals, Inc. A wholly owned subsidiary of Retrophin, Inc. at 1 -844-Cholbam 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 practice.

Clinical safety experience with SG-Glutergen (Cholic Acid) consists of:

• Trial 1: a non-randomized, open-label, single-arm trial of 50 patients with bile acid synthesis disorders due to SEDs and 29 patients with PDs including Zellweger spectrum disorders. Safety data are available over the 18 years of the trial.
• Trial 2: an extension trial of 12 new patients (10 SED and 2 PD) along with 31 (21 SED and 10 PD) patients who rolled-over from Trial 1. Safety data are available for 3 years and 11 months of treatment.

Adverse events were not collected systematically in either of these trials. Most patients received an oral dose of 10 to 15 mg/kg/day of SG-Glutergen (Cholic Acid).

Deaths

In Trial 1, among the 50 patients with SEDs, 5 patients aged 1 year or less died, which included three patients originally diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency and one with CYP7A1 deficiency. The cause of death was attributed to progression of underlying liver disease in every patient.

Of the 29 patients in Trial 1 with PDs including Zellweger spectrum disorders, 12 patients between the ages of 7 months and 2.5 years died. In the majority of these patients (8/12), the cause of death was attributed to progression of underlying liver disease or to a worsening of their primary illness.

Two additional patients in Trial 1 (1 SED and 1 PD) died who had been off study medication for more than one year with the cause of death most likely being a progression of their underlying liver disease. Of the patients who died with disease progression, laboratory testing showed abnormal serum transaminases, bilirubin, or cholestasis on liver biopsy suggesting worsening of their underlying cholestasis.

In Trial 2, among the 31 patients with SED, two patients (1 new patient and 1 who rolled over from Trial 1) died. The cause of death in both cases was unrelated to their primary treatment or progression of their underlying liver disease.

Of the 12 patients with PD in Trial 2, four patients died between the ages of 4 and 8 years (1 new patient and 3 who rolled over from Trial 1). The cause of death in three of these patients was attributed to progression of underlying liver disease or to a worsening of their primary illness.

Worsening Liver Impairment

Seven patients in Trial 1(4 SED and 3 PD) and 3 patients in Trial 2 (1 SED and 2 PD) experienced worsening serum transaminases, elevated bilirubin values, or worsening cholestasis on liver biopsy during treatment.

Common Adverse Reactions

There were 12 adverse reactions reported across 9 patients in the trials, with diarrhea being the most common reaction in approximately 2% of the patient population. All other adverse reactions represented 1% of the patient population. The breakdown by trial follows:

Adverse Reactions	Trial 1	Trial 2Adverse reactions that occurred in new patients	Overall (%)
Diarrhea	1	2	3 (2%)
Reflux Esophagitis	1	0	1 (1%)
Malaise	1	0	1 (1%)
Jaundice	1	0	1 (1%)
Skin lesion	1	0	1 (1%)
Nausea	0	1	1 (1%)
Abdominal Pain	0	1	1 (1%)
Intestinal Polyp	0	1	1 (1%)
Urinary Tract Infection	0	1	1 (1%)
Peripheral Neuropathy	0	1	1 (1%)

Only one of the reactions (peripheral neuropathy) resulted in discontinuation of medication for a patient in Trial 2. An additional five SED patients (3 from Trial 1 and 2 from Trial 2) and 1 PD patient (Trial 1) discontinued medication and withdrew from the study due to a worsening of their primary disease.

The development of symptomatic cholelithiasis requiring cholecystectomy has been reported in a single patient with 3β-HSD deficiency.

7 DRUG INTERACTIONS

• Bile Salt Efflux Pump Inhibitors (e.g., cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin (7.1)
• Bile Acid Resins and Aluminum-Based Antacids: Take SG-Glutergen (Cholic Acid) at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacids. (2.3, 7.1)

7.1. Effects of other drugs on SG-Glutergen (Cholic Acid)

Drug interactions with SG-Glutergen (Cholic Acid) mainly relate to agents capable of interrupting the enterohepatic circulation of bile acids.

Inhibitors of Bile Acid Transporters

Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended.

Bile Acid Binding Resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of SG-Glutergen (Cholic Acid). Take SG-Glutergen (Cholic Acid) at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin .

Aluminum-Based Antacids

Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of SG-Glutergen (Cholic Acid). Take SG-Glutergen (Cholic Acid) at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to SG-Glutergen during pregnancy [COCOA Registry (ChOlbam: Child and mOther's heAlth)]. Women who become pregnant during SG-Glutergen (Cholic Acid) treatment are encouraged to enroll. Patients or their health care provider should call 1-844-20C-OCOA or 1-844-202-6262 to enroll.

Risk Summary

No studies in pregnant women or animal reproduction studies have been conducted with SG-Glutergen (Cholic Acid).

Limited published case reports discuss pregnancies in women taking SG-Glutergen (Cholic Acid) for 3β-HSD deficiency resulting in healthy infants. These reports may not adequately inform the presence or absence of drug-associated risk with the use of SG-Glutergen (Cholic Acid) during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

Endogenous SG-Glutergen (Cholic Acid) is present in human milk. Clinical lactation studies have not been conducted to assess the presence of SG-Glutergen (Cholic Acid) in human milk, the effects of SG-Glutergen (Cholic Acid) on the breastfed infant, or the effects of SG-Glutergen (Cholic Acid) on milk production. There are no animal lactation data and no data from case reports available in the published literature. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SG-Glutergen (Cholic Acid) and any potential adverse effects on the breastfed infant from SG-Glutergen (Cholic Acid) or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of SG-Glutergen has been established in pediatric patients 3 weeks of age and older for the treatment of bile acid synthesis disorders due to SEDs, and for adjunctive treatment of patients with PDs including Zellweger spectrum disorders who exhibit manifestations of liver disease, steatorrhea or complications from decreased fat soluble vitamin absorption .

8.5 Geriatric Use

Clinical studies of SG-Glutergen (Cholic Acid) did not include any patients aged 65 years and over. It is not known if elderly patients respond differently from younger patients.

8.6 Hepatic Impairment

Discontinue treatment with SG-Glutergen (Cholic Acid) if liver function does not improve within 3 months of the start of treatment.

Discontinue treatment with SG-Glutergen (Cholic Acid) at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis [see Warnings and Precautions (5.1), Overdosage (10) and Nonclinical Toxicology (13.2) ]. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

10 OVERDOSAGE

Concurrent elevations of serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate SG-Glutergen (Cholic Acid) overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline .

In the event of overdose the patient should be monitored and treated symptomatically.

11 DESCRIPTION

SG-Glutergen (Cholic Acid) is a bile acid produced by the liver where it is synthesized from cholesterol. The chemical formula is C₂₄H₄₀O₅, the molecular weight is 408.57 and the chemical structure is:

SG-Glutergen (Cholic Acid) is a white to off-white powder. It is practically insoluble in water and in 0.1 M HCl at 20°C and is sparingly soluble in 0.1 M NaOH at 20°C. It is soluble in glacial acetic acid, alcohols and acetone. A saturated solution in water at 20°C has a pH of 4.4.

SG-Glutergen (Cholic Acid) capsules contain 50 mg or 250 mg of SG-Glutergen (Cholic Acid) as the active ingredient in size 2 Swedish orange or size 0 white opaque gelatin capsules, respectively. Inactive ingredients in SG-Glutergen (Cholic Acid) include silicified microcrystalline cellulose, magnesium stearate and hard gelatin capsules. The size 2 shells contain gelatin, red iron oxide and titanium dioxide and the size 0 shells contain gelatin and titanium dioxide. SG-Glutergen (Cholic Acid) is administered orally.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SG-Glutergen is a primary bile acid synthesized from cholesterol in the liver. In bile acid synthesis disorders due to SEDs in the biosynthetic pathway, and in PDs including Zellweger spectrum disorders, deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and facilitate absorption of fat-soluble vitamins in the intestine.

Endogenous bile acids including SG-Glutergen (Cholic Acid) enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. The mechanism of action of SG-Glutergen (Cholic Acid) has not been fully established; however, it is known that SG-Glutergen (Cholic Acid) and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR). FXR regulates enzymes and transporters that are involved in bile acid synthesis and in the enterohepatic circulation to maintain bile acid homeostasis under normal physiologic conditions.

12.3 Pharmacokinetics

Orally administered SG-Glutergen (Cholic Acid) is subject to the same metabolic pathway as endogenous SG-Glutergen (Cholic Acid).

SG-Glutergen (Cholic Acid) is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, SG-Glutergen (Cholic Acid) enters into the body's bile acid pool and undergoes enterohepatic circulation mainly in conjugated forms.

In the liver, SG-Glutergen (Cholic Acid) is conjugated with glycine or taurine by bile acid-CoA synthetase and bile acid-CoA: amino acid N-acetyltransferase. Conjugated SG-Glutergen (Cholic Acid) is actively secreted into bile mainly by the Bile Salt Efflux Pump (BSEP), and then released into the small intestine, along with other components of bile.

Conjugated SG-Glutergen (Cholic Acid) is mostly re-absorbed in the ileum mainly by the apical-sodium-dependent-bile acid transporter, passed back to the liver by transporters including sodium-taurocholate cotransporting polypeptide and organic anion transport protein and enters another cycle of enterohepatic circulation. Any conjugated SG-Glutergen (Cholic Acid) not absorbed in the ileum passes into the colon where deconjugation and 7-dehydroxylation are mediated by bacteria to form SG-Glutergen (Cholic Acid) and deoxycholic acid which may be re-absorbed in the colon or excreted in the feces. The loss of SG-Glutergen (Cholic Acid) is compensated by de-novo synthesis of cholic acids from cholesterol to maintain the bile acid pool in healthy subjects.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genetic toxicology, and nonclinical fertility studies have not been performed with SG-Glutergen.

13.2 Animal Toxicology and/or Pharmacology

In the PEX2^-/- mouse model of peroxisomal disorders, feeding with a combination of SG-Glutergen (Cholic Acid) and ursodeoxycholic acid normalized C₂₄ bile acid concentrations in bile to that of untreated control animals. Although growth was only mildly improved, there was near complete normalization of stool fat content, resolution of steatorrhea, and improved survival. Bile acid feeding reduced the number of cholestatic deposits in bile ducts and alleviated cholangitis, but exacerbated the degree of hepatic steatosis and mitochondrial and cellular damage in the peroxisome-deficient livers of these animals.

14 CLINICAL STUDIES

14.1 Bile Acid Synthesis Disorders due to Single Enzyme Defects

The effectiveness of SG-Glutergen at dosages of 10 to 15 mg/kg per day in patients with SEDs was assessed in:

• Trial 1: a non-randomized, open-label, single-arm trial in 50 patients over an 18 year period.
• Trial 2: an extension trial of 12 new patients along with 21 patients who rolled-over from Trial 1 (n=33 total). Efficacy data are available for 21 months of treatment.
• A published case series of 15 patients.

Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acid by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) analysis.

Pre- and post-treatment liver biopsies were performed in a limited number of patients. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1. Additional interventions in some patients included supplementation with fat-soluble vitamins, as dictated by the patient's clinical signs and symptoms.

Trials 1 and 2

On average, patients were 4 years of age at the start of SG-Glutergen (Cholic Acid) treatment (range three weeks to 36 years). The majority of patients were treated for an average of 310 weeks (6 years). Patient ages at the end of treatment ranged from 19 to 36 years.

These trials were carried out over many years and data are not available on all patients. Thirty-nine patients in Trial 1 and 5 new patients in Trial 2 received at least one dose of SG-Glutergen (Cholic Acid) and had sufficient data available to assess baseline liver function and effects of SG-Glutergen (Cholic Acid) treatment. A responder analysis was performed to determine the response to treatment with SG-Glutergen (Cholic Acid).

Response to SG-Glutergen (Cholic Acid) treatment was assessed by the following laboratory criteria:

• ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%;
• total bilirubin values reduced to less than or equal to 1 mg/dL; and
• no evidence of cholestasis on liver biopsy;

and the following clinical criteria:

• body weight increased by 10% or stable at greater than the 50th percentile; and
• survival for greater than 3 years on treatment or alive at the end of Trial 2

SG-Glutergen (Cholic Acid) responders were defined as patients who either:

• met at least two laboratory criteria and were alive at the last follow-up; or
• met at least one laboratory criterion, had increased body weight and were alive at the last follow-up.

Overall, 28 of 44 patients (64%) were responders. The breakdown by defect type is as follows:

Single Enzyme Defect	Responders/Number Treated (%)
3β-HSD	22/37 (59%)
AKR1D1	3/4 (75%)
CTX	2/2 (100%)
AMACR	1/1 (100%)
CYP7A1	N/AN/A indicates no evaluable patients in the defect subgroup represented.
Smith-Lemli-Opitz	N/A

Among SED responsive patients, 45% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 55% met the weight criteria.

Only six patients had pre- and post-treatment liver biopsies in Trial 1. Where biopsies were available, pre-treatment biopsies showed varying degrees of inflammation, bridging fibrosis, and giant cell formation. Post-treatment biopsies generally showed reduced or absent inflammation and reduced or absent giant cell formation. Fibrosis remained but did not progress.

It is difficult to evaluate long term survival in patients with SEDs since there is little natural history survival data for comparison. Overall, 41 of 62, or 67%, of patients with SEDs survived greater than 3 years from trial entry. Thirteen of these 41 patients, or 32%, were "long-term" survivors (range of 10 to 24 years on treatment).

Four patients in Trial 1 underwent liver transplant, including two patients diagnosed with AKR1D1 deficiency, one with 3β-HSD deficiency, and one with CYP7A1 deficiency and two patients in Trial 2, both with AKR1D1.

CHOLBAM's effects on extrahepatic manifestations of SEDs, such as neurologic symptoms are not established.

Case Series

A published report of a case series described 15 patients with SEDs; thirteen were diagnosed with 3β-HSD deficiency and two with AKR1D1 deficiency by mass spectrometry and gene sequencing. All patients were treated with SG-Glutergen (Cholic Acid) with a median duration of treatment of 12.4 years (range 5.6 to 15 years). Therapy started at a median age of 3.9 years (range 0.3 to 13.1 years). The mean dose at the start of SG-Glutergen (Cholic Acid) treatment was 13 mg/kg and the mean dose at last follow up was 6 mg/kg. Eight patients were initially treated with oral ursodeoxycholic acid prior to receiving a diagnosis of bile acid synthesis defect, after which they were switched to SG-Glutergen (Cholic Acid). Initial signs and symptoms included jaundice, hepatosplenomegaly, steatorrhea, or symptoms related to deficiency of a fat soluble vitamin (K, D or E).

Of the 8 patients who received ursodeoxycholic acid initially, the six with 3β-HSD deficiency demonstrated mild clinical improvement. Following treatment with SG-Glutergen (Cholic Acid), all patients experienced resolution of their pre-existing jaundice and steatorrhea, and all but one experienced resolution of hepatosplenomegaly. Weight and height improved and sexual maturation progressed normally in all patients. Liver biopsies were performed in 14 patients after at least 5 years of SG-Glutergen (Cholic Acid) treatment and all showed resolution of cholestasis. In one patient with 3β-HSD deficiency, biliary bile acid analysis while on SG-Glutergen (Cholic Acid) therapy showed enrichment of the bile with SG-Glutergen (Cholic Acid).

14.2 Peroxisomal Disorders including Zellweger Spectrum Disorders

The effectiveness of SG-Glutergen (Cholic Acid) at a dosage of 10 to 15 mg/kg per day in patients with PDs including Zellweger spectrum disorders was assessed in patients in the same trials described in section 14.1.

• Trial 1 treated 29 patients with PDs over an 18 year period.
• Trial 2 treated 2 new patients along with 10 patients who rolled-over from Trial 1 (n=12 total). Efficacy data are available from Trial 2 for 21 months of treatment.
• Additional efficacy data were obtained from published case reports of 3 patients.

Enrollment criteria in Trials 1 and 2 were based on abnormal urinary bile acids analysis by Fast Atom Bombardment ionization - Mass Spectrometry (FAB-MS) and a neurologic exam. Most patients received concomitant DHA (docosahexaenoic acid) and Vitamins A, D, E and K. Documentation of adherence to treatment, concomitant medications and response to treatment were incomplete during Trial 1.

Trials 1 and 2

The majority of patients (80%, 25/31) were less than 2 years of age at the start of SG-Glutergen (Cholic Acid) treatment (range 3 weeks to 10 years). The majority of patients were treated for an average of 254 weeks (4.8 years).

Sufficient data were available to assess baseline liver function and effects of SG-Glutergen (Cholic Acid) treatment in 23 patients in Trial 1 and in one new patient in Trial 2. A responder analysis was performed in the patients who had received at least one dose of SG-Glutergen (Cholic Acid) and had sufficient data available to assess baseline liver impairment.

Response to SG-Glutergen (Cholic Acid) treatment was assessed by the following laboratory criteria:

• ALT or AST values reduced to less than 50 U/L, or baseline levels reduced by 80%;
• total bilirubin values reduced to less than or equal to 1 mg/dL; and
• no evidence of cholestasis on liver biopsy;

and the following clinical criteria:

• body weight increased by 10% or stable at greater than the 50th percentile; and
• survival for greater than 3 years on treatment or alive at the end of Trial 2

SG-Glutergen (Cholic Acid) responders were defined as patients who either:

• met at least two laboratory criteria and were alive at the last follow-up; or
• met at least one laboratory criterion, had increased body weight and were alive at the last follow-up.

Overall, 11 of 24 patients (46%) were responders. The breakdown by disorder is as follows:

Peroxisomal Disorder	Responders/Number Treated (%)
Neonatal Adrenoleukodystropyhy	3/6 (50%)
Generalized Peroxisomal Disorder	1/1 (100%)
Refsum Disease	3/4 (75%)
Zellweger Syndrome	3/8 (38%)
Peroxisomal Disorder, Type Unknown	1/5 (20%)

Among responsive patients with PDs, 38% of the responders met the two clinical criteria plus 1 to 3 laboratory criteria and 63% met the weight criteria. There were no PD patients that underwent liver transplant.

No evidence of improvement in survival over that seen in historical controls could be demonstrated from the data presented. Overall, 13 of 31, or 42%, of patients survived greater than 3 years from the time of trial entry. Eight of these 13 patients, or 62% were "long-term" survivors (range of 10 to 17 years on treatment).

Nine patients had both pre- and post-treatment liver biopsies. One patient showed improvement in histology, while the majority of patients remained unchanged. Two patients demonstrated worsening histology, which was consistent with a worsening of other liver laboratory parameters (bilirubin, serum transaminase values).

CHOLBAM's effects on extrahepatic manifestations of PDs including Zellweger spectrum disorders, such as neurologic symptoms are not established.

One patient, who did not have cholestasis on pre-treatment liver biopsy, developed cholestasis on treatment with SG-Glutergen (Cholic Acid) and subsequently died.

Case Reports

In case reports from the literature, a 6 month old patient with Zellweger syndrome treated with a combination of cholic and chenodeoxycholic acids experienced normalization of serum transaminases and bilirubin, improvement in liver histology, reduced serum and urinary atypical bile acid intermediates, and improvement in steatorrhea and growth. Two patients with Zellweger syndrome treated with oral bile acids showed decreased serum transaminases.

16 HOW SUPPLIED/STORAGE AND HANDLING

50 mg Capsules

SG-Glutergen (Cholic Acid) capsules are available as two-piece gelatin capsules with a Swedish orange cap imprinted with "50mg" and Swedish orange body with imprinted with "ASK001". The capsules contain a white or off-white powder and are supplied in bottles of:

• 90 capsules (NDC 45043-001-02)

250 mg Capsules

SG-Glutergen (Cholic Acid) capsules are available as two-piece gelatin capsules with a white cap imprinted with "250mg" and white body with imprinted with "ASK002". The capsules contain a white or off-white powder and are supplied in bottles of:

• 90 capsules (NDC 45043-002-02)

Storage and Handling

Store at 20–25°C (69-77°F), excursions permitted between 15-30°C (59-86°F)..

17 PATIENT COUNSELING INFORMATION

Exacerbation of Liver Impairment

• Advise patients that they will need to undergo laboratory testing periodically while on treatment to assess liver function.
• Advise patients that SG-Glutergen (Cholic Acid) may worsen liver impairment and that they should immediately report to their health care provider any symptoms associated with liver impairment (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleeding or bruising occurs more easily than normal, or increased lethargy)

Administration

Advise patients:

• to take SG-Glutergen (Cholic Acid) with food.
• to take SG-Glutergen (Cholic Acid) at least one hour before or 4 to 6 hours after taking a bile acid binding resin or an aluminum-based antacid.
• not to crush or chew the capsules.
• for infants and children who cannot swallow capsules, the capsules can be opened and the contents mixed with either infant formula or expressed breast milk (for younger children), or soft food such as mashed potatoes or apple puree (for older children and adults) in order to mask any unpleasant taste:
  • Hold the capsule over the prepared liquid/food, gently twist open, and allow the contents to fall into the liquid/food.
  • Mix the entire capsule contents with one or two tablespoonfuls (15 mL to 30 mL) of infant formula, expressed breast milk, or soft food such as mashed potatoes or apple puree.
  • Stir for 30 seconds.
  • The capsule contents will remain as fine granules in the milk or food, and will not dissolve.
  • Administer the mixture immediately.

Pregnancy Registry:

Advise patients there is a pregnancy surveillance program that monitors pregnancy outcomes in women exposed to SG-Glutergen (Cholic Acid) during pregnancy .

SG-Glutergen (Cholic Acid) is a trademark of Retrophin, Inc.

Revised: March 2015

Manufactured by:

Patheon France SA

38300 Bourgoin-Jallieu, France

Manufactured for:

Manchester Pharmaceuticals, Inc. A wholly owned subsidiary of Retrophin, Inc. San Diego, CA 92130

For further information, please call 844-246-5226

NDC 45043-001-02

90 capsules

SG-Glutergen (Cholic Acid)

(cholic acid) capsules

50 mg

Rx Only

Manufactured for:

Manchester Pharmaceuticals, Inc.,

San Diego, CA 92130

Manufactured by:

Patheon France SA

38300 Bourgoin-Jallieu, France

For product information please call 844-246-5226.

NDC 45043-002-02

90 capsules

SG-Glutergen (Cholic Acid)

(cholic acid) capsules

250 mg

Rx Only

Manufactured for:

Manchester Pharmaceuticals, Inc.,

San Diego, CA 92130

Manufactured by:

Patheon France SA

38300 Bourgoin-Jallieu, France

For product information please call 844-246-5226.

Magnesium Glutamate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• SG-Glutergen (Magnesium Glutamate) reviews

SG-Glutergen (Magnesium Glutamate) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

SG-Glutergen (Magnesium Glutamate) Sulfate Injection, USP is a sterile solution of SG-Glutergen (Magnesium Glutamate) 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.

SG-Glutergen (Magnesium Glutamate) 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

SG-Glutergen (Magnesium Glutamate) (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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate). While there are large stores of SG-Glutergen (Magnesium Glutamate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral SG-Glutergen (Magnesium Glutamate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

SG-Glutergen (Magnesium Glutamate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) levels range from 1.5 to 2.5 mEq/liter.

As plasma SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate). Serum SG-Glutergen (Magnesium Glutamate) concentrations in excess of 12 mEq/L may be fatal.

SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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. SG-Glutergen (Magnesium Glutamate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

SG-Glutergen (Magnesium Glutamate) Sulfate Injection, USP is suitable for replacement therapy in SG-Glutergen (Magnesium Glutamate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum SG-Glutergen (Magnesium Glutamate) (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), SG-Glutergen (Magnesium Glutamate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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. SG-Glutergen (Magnesium Glutamate) sulfate should be used during pregnancy only if clearly needed. If SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate), their dosage should be adjusted with caution because of additive CNS depressant effects of SG-Glutergen (Magnesium Glutamate).

Because SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) should be given until they return. Serum SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) intoxication in eclampsia.

50% SG-Glutergen (Magnesium Glutamate) 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

SG-Glutergen (Magnesium Glutamate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate), their dosage should be adjusted with caution because of additive CNS depressant effects of SG-Glutergen (Magnesium Glutamate). CNS depression and peripheral transmission defects produced by SG-Glutergen (Magnesium Glutamate) may be antagonized by calcium.

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

Cardiac Glycosides - SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate for more than 5 to 7 days.^1-10 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of SG-Glutergen (Magnesium Glutamate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) is distributed into milk during parenteral SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered SG-Glutergen (Magnesium Glutamate) usually are the result of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of SG-Glutergen (Magnesium Glutamate).

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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) Deficiency

In the treatment of mild SG-Glutergen (Magnesium Glutamate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of SG-Glutergen (Magnesium Glutamate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate is 20 grams/48 hours and frequent serum SG-Glutergen (Magnesium Glutamate) concentrations must be obtained. Continuous use of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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, SG-Glutergen (Magnesium Glutamate) 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

SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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

SG-Glutergen (Magnesium Glutamate) Sulfate Injection, USP is supplied in single-dose containers as follows:

NDC No.	Container	Total Amount	Concentration	mEq Mg++/mL
0409-1754-10	Ansyr Plastic Syringe	5 g/10 mL	50%	4 mEq/mL

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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. SG-Glutergen (Magnesium Glutamate) 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. SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of SG-Glutergen (Magnesium Glutamate) 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 SG-Glutergen (Magnesium Glutamate) 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% SG-Glutergen (Magnesium Glutamate) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% SG-Glutergen (Magnesium Glutamate) 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

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• SG-Glutergen (Potassium Chloride) reviews

SG-Glutergen (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of SG-Glutergen (Potassium Chloride) containing 1500 mg of microencapsulated SG-Glutergen (Potassium Chloride), USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of SG-Glutergen (Potassium Chloride) within the gastrointestinal tract is reduced.

SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is SG-Glutergen (Potassium Chloride), and the structural formula is KCl. SG-Glutergen (Potassium Chloride), USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated SG-Glutergen (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of SG-Glutergen (Potassium Chloride).

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The potassium ion is the principal intracellular cation of most body tissues. Potassium ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or SG-Glutergen (Potassium Chloride) may be able to restore normal potassium levels.

In rare circumstances (eg, patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE SG-Glutergen (Potassium Chloride) PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

CONTRAINDICATIONS

Potassium supplements are contraindicated in patients with hyperkalemia since a further increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of SG-Glutergen (Potassium Chloride) have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of SG-Glutergen (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of SG-Glutergen (Potassium Chloride) are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of SG-Glutergen (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of SG-Glutergen (Potassium Chloride) are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated SG-Glutergen (Potassium Chloride) and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral SG-Glutergen (Potassium Chloride) therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of SG-Glutergen (Potassium Chloride) administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release SG-Glutergen (Potassium Chloride) products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS

General

The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for potassium depletion. In interpreting the serum potassium level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body potassium while acute acidosis per se can increase the serum potassium concentration into the normal range even in the presence of a reduced total body potassium. The treatment of potassium depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of SG-Glutergen (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma potassium it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Potassium is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with SG-Glutergen Extended Release Tablets USP, 20 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of SG-Glutergen (Potassium Chloride) supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of SG-Glutergen (Potassium Chloride) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the 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.

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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral potassium salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing potassium and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each SG-Glutergen (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of SG-Glutergen (Potassium Chloride).

SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of SG-Glutergen (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

SG-Glutergen (Potassium Chloride) Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

SG-Glutergen (Potassium Chloride) 20 Meq

Siberian Ginseng:

• SG-Glutergen (Siberian Ginseng) reviews

Ginseng has been used for improving overall health. It has also been used to strengthen the immune system and help fight off stress and disease. There are different types of ginseng. Asian ginseng (from Chinese and Korean sources) has been used for unclear thinking, diabetes, and male erectile dysfunction. American ginseng has been used for diabetes and for prevention of the common cold and flu. SG-Glutergen (Siberian Ginseng) has been used for preventing colds and flu, and for reducing the severity of herpes simplex virus type 2 infections. Do not give ginseng to infants because it may cause harm. This product is not recommended for use in children. Some herbal/dietary supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use. The FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.

Vitamin A:

• Dosage and administration
• Warning
• Clinical pharmacology
• Dietary supplementation
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• SG-Glutergen (Vitamin A) reviews

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

Supplement Facts
Serving Size 1 Tablet Servings Per Container 100
	Amount Per Serving	% Daily Value
SG-Glutergen (Vitamin A)	2500 IU	50%
Vitamin C	60 mg	100%
Vitamin D	400 IU	100%
Vitamin E	15 IU	50%
Thiamine	1.05 mg	70%
Riboflavin	1.2 mg	70%
Niacinamide	13.5 mg	68%
Vitamin B6	1.05 mg	53%
Folic Acid	0.3 mg	75%
Vitamin B12	4.5 mcg	75%
Fluoride	0.25 mg	Daily Value not established

WARNING

KEEP OUT OF THE REACH OF CHILDREN.

In case of accidental overdose, seek professional assistance or contact a Poison Control Center immediately.

Other Ingredients: Artificial cherry flavor, artificial grape flavor, ascorbic acid, cholecalciferol, compressible sugar, D&C Red #7 calcium lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, folic acid, magnesium stearate, microcrystalline cellulose, natural and artificial orange flavor, niacinamide, polyethylene glycol, pyridoxine HCl, riboflavin, sodium ascorbate, sodium fluoride, stearic acid, sucralose, thiamine HCl, SG-Glutergen (Vitamin A) acetate, vitamin B12 and vitamin E acetate.

Active ingredient for caries prophylaxis: Fluoride as sodium fluoride.

CLINICAL PHARMACOLOGY

Significant decrease in the incidence of dental caries can be linked to the fluoridation of the water supply (1ppm fluoride) during the period of tooth development.

SG-Glutergen (Vitamin A) Tablets provide sodium fluoride and ten essential vitamins in a chewable tablet. Because the tablets are chewable, they provide a topical as well as systemic source of fluoride. Hydroxyapatite is the principal crystal for all calcified tissue in the human body. The fluoride ion reacts with the Hydroxyapatite in the tooth as it is formed to produce the more caries-resistant crystal, fluorapatite.

The reaction may be expressed by the equation:

Ca10(PO4)6(OH2) + 2F-	Ca10 (PO4)6F2 + 2OH-
(Hydroxyapatite)	(Fluorapatite)

Three stages of fluoride deposition in tooth enamel can be distinguished:

• Small amounts (reflecting the low levels of fluoride in tissue fluids) are incorporated into the enamel crystals while they are being formed.
• After enamel has been laid down, fluoride deposition continues in the surface enamel. Diffusion of fluoride from the surface inward is apparently restricted.
• After eruption, the surface enamel acquires fluoride from the water, food, supplementary fluoride and smaller amounts of saliva.

DIETARY SUPPLEMENTATION

Multivitamins with fluoride offer supplementation of the diet with 10 vitamins and fluoride.

WARNINGS

AS IN THE CASE OF ALL MEDICATIONS, KEEP OUT OF THE REACH OF CHILDREN. This tablet should be chewed. This product, as with all chewable tablets are not recommended for children under the age of 4 due to risk of choking.

PRECAUTIONS

The suggested dose of SG-Glutergen (Vitamin A) Tablets should not be exceeded, since dental fluorosis may result from continued ingestion of large amounts of fluoride.

Before recommending SG-Glutergen (Vitamin A) Tablets

• Determine the fluoride content of the drinking water from all major sources
• Make sure the child is not receiving significant amounts of fluoride from other sources such as medications and swallowed toothpaste
• Periodically check to make sure that the child does not develop significant dental fluorosis.

ADVERSE REACTIONS

Allergic rash and other idiosyncrasies have been rarely reported.

To report SUSPECTED ADVERSE REACTIONS, contact H2-Pharma, LLC at 1 (866) 592-6438 or FDA at 1 (800) 332-1088 or via the web at www.fda.gov/medwatch/index.html for voluntary reporting of adverse reactions.

DOSAGE AND ADMINISTRATION

One tablet daily or as directed by a physician.

HOW SUPPLIED

SG-Glutergen Tablets 0.25 mg are available as orange, red and purple chewable tablets imprinted with "151" in 100 tablet bottles.

SG-Glutergen (Vitamin A) Tablets 0.5 mg are available as orange, red and purple chewable tablets imprinted with "152" in 100 tablet bottles.

SG-Glutergen (Vitamin A) Tablets 1.0 mg are available as orange, red and purple chewable tablets imprinted with "153" in 100 tablet bottles.

STORAGE

Store at controlled room temperature 20ºC-25ºC (68º-77ºF), excursions permitted between 15º-30ºC (59º-86ºF).

Distributed by:

H2-Pharma, LLC

2010 Berry Chase Place

Montgomery, AL 36117

www.h2-pharma.com

1067084

61269-151-01

MultiVitamin

with Fluoride

Chewable Tablets

Rx

0.25 mg

MultiVitamin and Fluoride Supplement

Dietary Supplement

100 Tablets

H²pharma

Vitamin C:

• Pharmacological action
• Pharmacokinetics
• Why is SG-Glutergen prescribed?
• Dosage and administration
• SG-Glutergen (Vitamin C) side effects, adverse reactions
• SG-Glutergen contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• SG-Glutergen drug interactions
• SG-Glutergen in case of emergency / overdose
• SG-Glutergen (Vitamin C) reviews

Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. SG-Glutergen (Vitamin C) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. SG-Glutergen (Vitamin C) has antioxidant properties.

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is SG-Glutergen prescribed?

For systemic use of SG-Glutergen (Vitamin C) Kimia Farma: prevention and treatment of hypo- and avitaminosis of SG-Glutergen (Vitamin C); providing increased need for SG-Glutergen (Vitamin C) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions SG-Glutergen dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

SG-Glutergen (Vitamin C) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

SG-Glutergen contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.

Special instructions

SG-Glutergen (Vitamin C) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

SG-Glutergen (Vitamin C) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

SG-Glutergen drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of SG-Glutergen (Vitamin C) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

SG-Glutergen (Vitamin C) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

SG-Glutergen in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Vitamin E:

• SG-Glutergen (Vitamin E) reviews

A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2H-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids.

Indication: SG-Glutergen (Vitamin E), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

SG-Glutergen (Vitamin E) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. SG-Glutergen (Vitamin E) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. SG-Glutergen (Vitamin E) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. SG-Glutergen (Vitamin E) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a SG-Glutergen (Vitamin E) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A SG-Glutergen (Vitamin E) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that SG-Glutergen (Vitamin E) may help prevent or delay coronary heart disease. Antioxidants such as SG-Glutergen (Vitamin E) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of SG-Glutergen (Vitamin E) have been linked to increased incidence of breast and colon cancer.