Tonar

Calcium:

• 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
• Tonar (Calcium) reviews

1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Tonar (Calcium) acetate capsule.

- Capsule: 667 mg Tonar (Calcium) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

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

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

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

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

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

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

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

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

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

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

6.1 Clinical Trial Experience

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

In clinical studies, Tonar (Calcium) acetate has been generally well tolerated.

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

Preferred Term	Total adverse reactions reported for Tonar (Calcium) acetate N=167 N (%)	3 month, open label study of Tonar (Calcium) acetate N=98 N (%)	Double blind, placebo-controlled, cross-over study of liquid Tonar (Calcium) acetate N=69
			Tonar (Calcium) acetate N (%)	Placebo N (%)
Nausea	6 (3.6)	6 (6.1)	0 (0)	0 (0)
Vomiting	4 (2.4)	4 (4.1)	0 (0)	0 (0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0)

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

6.2 Postmarketing Experience

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

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

7 DRUG INTERACTIONS

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

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

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

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

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

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

8.2 Labor and Delivery

The effects of Tonar (Calcium) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

10 OVERDOSAGE

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

11 DESCRIPTION

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

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

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

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

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

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

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

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

* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE.
Parameter	Pre-Study	Week 4*	Week 8	Week 12	p-value†
Phosphorus (mg/dL)‡	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Tonar (Calcium) (mg/dL)‡	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

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

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

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

* ANOVA of Tonar (Calcium) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM.
Parameter	Pre-Study	Post-Treatment		p-value*
		Tonar (Calcium) Acetate	Placebo
Phosphorus (mg/dL)†	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Tonar (Calcium) (mg/dL)†	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Tonar (Calcium) Acetate Capsules

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

NDC 0615-2303-39: Blistercards of 30 Capsules

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

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

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

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

L-Histidine:

• Tonar (L-Histidine) reviews

An essential amino acid that is required for the production of histamine.

Indication: The actions of supplemental Tonar (L-Histidine) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Tonar (L-Histidine) may be indicated for use in some with rheumatoid arthritis. It is not indicated for treatment of anemia or uremia or for lowering serum cholesterol.

Is found abundantly in hemoglobin; has been used in the treatment of rheumatoid arthritis, allergic diseases, ulcers and anemia. A deficiency can cause poor hearing.

L-Lysine Acetate:

• Tonar (L-Lysine Acetate) reviews

Tonar (L-Lysine Acetate) (abbreviated as Lys or K) is an О±-amino acid with the chemical formula HO2CCH(CH2)4NH2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.L-Lysine is a base, as are arginine and histidine. The Оµ-amino group often participates in hydrogen bonding and as a general base in catalysis. Common posttranslational modifications include methylation of the Оµ-amino group, giving methyl-, dimethyl-, and trimethyllysine. The latter occurs in calmodulin. Other posttranslational modifications include acetylation. Collagen contains hydroxylysine which is derived from lysine by lysyl hydroxylase. O-Glycosylation of lysine residues in the endoplasmic reticulum or Golgi apparatus is used to mark certain proteins for secretion from the cell.

Indication: Supplemental Tonar (L-Lysine Acetate) has putative anti-herpes simplex virus activity. There is preliminary research suggesting that it may have some anti-osteoporotic activity.

Insures the adequate absorption of calcium; helps form collagen ( which makes up bone cartilage & connective tissues); aids in the production of antibodies, hormones & enzymes. Recent studies have shown that Lysine may be effective against herpes by improving the balance of nutrients that reduce viral growth. A deficiency may result in tiredness, inability to concentrate, irritability, bloodshot eyes, retarded growth, hair loss, anemia & reproductive problems.

L-Threonine:

• Tonar (L-Threonine) reviews

An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.

Indication: Tonar (L-Threonine) makes up collagen, elastin, and enamel protein. It aids proper fat metabolism in the liver, helps the digestive and intestinal tracts function more smoothly, and assists in metabolism and assimilation.

Tonar (L-Threonine) is an essential amino acid that helps to maintain the proper protein balance in the body. It is important for the formation of collagen, elastin, and tooth enamel, and aids liver and lipotropic function when combined with aspartic acid and methionine.

L-Tryptophan:

• Tonar (L-Tryptophan) reviews

An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor of indole alkaloids in plants. It is a precursor of serotonin (hence its use as an antidepressant and sleep aid). It can be a precursor to niacin, albeit inefficiently, in mammals.

Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.

Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).

L-Tyrosine:

• Tonar (L-Tyrosine) reviews

A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin.

Indication: Tyrosine is claimed to act as an effective antidepressant, however results are mixed. Tyrosine has also been claimed to reduce stress and combat narcolepsy and chronic fatigue, however these claims have been refuted by some studies.

Tyrosine is a nonessential amino acid synthesized in the body from phenylalanine. Tyrosine is critical for the production of the body's proteins, enzymes and muscle tissue. Tyrosine is a precursor to the neurotransmitters norepinephrine and dopamine. It can act as a mood elevator and an anti-depressant. It may improve memory and increase mental alertness. Tyrosine aids in the production of melanin and plays a critical role in the production of thyroxin (thyroid hormones). Tyrosine deficiencies are manifested by hypothyroidism, low blood pressure and low body temperature. Supplemental tyrosine has been used to reduce stress and combat narcolepsy and chronic fatigue.

Nitrogen:

• Nitrogen nf coa
• Tonar (Nitrogen) reviews

REFRIGERATED LIQUID

Tonar (Nitrogen), REFRIGERATED LIQUID NF UN1977 NON-FLAMMABLE GAS 2 41977 (R 04/11)

Rx only

WARNING: Administration of Tonar (Nitrogen) may be hazardous or contraindicated. For use only by or under the supervision

of a licensed practitioner who is experienced in the use and administration of Tonar (Nitrogen) and is familiar with the

indications, effects, dosages, methods, and frequency and duration of administration,and with the hazards,

contraindications, and side effects and the precautions to be taken.

ALWAYS KEEP CONTAINER IN UPRIGHT POSITION.

DO NOT CHANGE OR FORCE FIT CONNECTIONS.

WARNING:

EXTREMELY COLD LIQUID AND GAS UNDER PRESSURE.

CAN CAUSE RAPID SUFFOCATION.

CAN CAUSE SEVERE FROSTBITE.

Store and use with adequate ventilation.

Do not get liquid in eyes, on skin or clothing.

For liquid withdraw, wear face shield and gloves.

Do not drop. Use suitable hand truck for container movement.

Cylinder temperature should not exceed 52 degrees C (125 degrees F).

Close valve after each use and when empty.

Use a back flow preventive device in the piping.

Use in accordance with the Material Safety Data Sheet (MSDS).

FIRST AID:

IF INHALED, remove to fresh air. If not breathing, give artificial respiration. If breathing, give oxygen.

Call a physician.

FIRST AID: IN CASE OF FROSTBITE, obtain medical treatment immediately.

CAS: 7727-37-9

DO NOT REMOVE THIS PRODUCT LABEL.

NORCO 1125 West Amity Boise, Idaho, 83705 (208) 336-1643

USPUN1977

Tonar NF COA

Norco n2 COA

Tonar (Nitrogen) COMPRESSED NF UN1066 NON-FLAMMABLE GAS 2 41066 (R 04/11)

WARNING: Secure all cylinders while in storage and in use.

Rx only

WARNING: Administration of Tonar (Nitrogen) may be hazardous or contraindicated. For use only by or under the supervision

of a licensed practitioner who is experienced in the use and administration of Tonar (Nitrogen) and is familiar with the

indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards,

contraindications, and side effects and the precautions to be taken.

CAUTION: HIGH PRESSURE GAS. CAN CAUSE RAPID SUFFOCATION.

Store and use with adequate ventilation. Use a back flow preventive device in the piping. Cylinder temperature should

not exceed 52 degrees C (125 degrees F). Close valve after each use and when empty. Use in accordance with the

Material Safety Data Sheet (MSDS).

FIRST AID: IF INHALED, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult,

give oxygen. Call a physician.

CAS: 7727-37-9

DO NOT REMOVE THIS PRODUCT LABEL

CONTENT_________________ LOT#_________________

NORCO 1125 W. Amity Rd. Boise, Idaho 83705 (208) 336-1643

USPUN1066