Comb Q Homoeopathic

Iron (Ferrous Phosphate):

• 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
• Comb Q Homoeopathic (Iron (Ferrous Phosphate)) reviews

1 INDICATIONS AND USAGE

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is indicated for the treatment of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency anemia in patients with chronic kidney disease (CKD).

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is an Comb Q Homoeopathic (Iron (Ferrous Phosphate)) replacement product indicated for the treatment of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Comb Q Homoeopathic ) must only be administered intravenously either by slow injection or by infusion. The dosage of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is expressed in mg of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Each mL contains 20 mg of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)).

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) should be administered early during the dialysis session. The usual total treatment course of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is 1000 mg. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment may be repeated if Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Comb Q Homoeopathic (Iron (Ferrous Phosphate)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment may be repeated if Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in a maximum of 250 mL of 0.9% NaCl. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment may be repeated if Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment

The dosing for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment: Administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment

The dosing for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment: Administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Comb Q Homoeopathic (Iron (Ferrous Phosphate))

• Known hypersensitivity to Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Comb Q Homoeopathic ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Comb Q Homoeopathic (Iron (Ferrous Phosphate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)). (5.2)
• Comb Q Homoeopathic (Iron (Ferrous Phosphate)) Overload: Regularly monitor hematologic responses during Comb Q Homoeopathic (Iron (Ferrous Phosphate)) therapy. Do not administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) to patients with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Comb Q Homoeopathic (Iron (Ferrous Phosphate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Comb Q Homoeopathic (Iron (Ferrous Phosphate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Comb Q Homoeopathic (Iron (Ferrous Phosphate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Comb Q Homoeopathic ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Hypotension following administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) may be related to the rate of administration and/or total dose administered .

5.3 Comb Q Homoeopathic (Iron (Ferrous Phosphate)) Overload

Excessive therapy with parenteral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) can lead to excess storage of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Comb Q Homoeopathic (Iron (Ferrous Phosphate)) require periodic monitoring of hematologic and Comb Q Homoeopathic (Iron (Ferrous Phosphate)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) to patients with evidence of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose; do not perform serum Comb Q Homoeopathic (Iron (Ferrous Phosphate)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Comb Q Homoeopathic ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Comb Q Homoeopathic ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Comb Q Homoeopathic (Iron (Ferrous Phosphate)) therapy and were reported to be intolerant (defined as precluding further use of that Comb Q Homoeopathic (Iron (Ferrous Phosphate)) product). When these patients were treated with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) there were no occurrences of adverse reactions that precluded further use of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 0.5 mg/kg group, 10 (21%) patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 1.0 mg/kg group, and 10 (21%) patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

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

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) injection. Reactions have occurred following the first dose or subsequent doses of Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Comb Q Homoeopathic (Iron (Ferrous Phosphate)) have not been studied. However, Comb Q Homoeopathic (Iron (Ferrous Phosphate)) may reduce the absorption of concomitantly administered oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Comb Q Homoeopathic ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose. Because animal reproductive studies are not always predictive of human response, Comb Q Homoeopathic (Iron (Ferrous Phosphate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose is excreted in human milk. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Comb Q Homoeopathic ) for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) has not been studied in patients younger than 2 years of age.

In a country where Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Comb Q Homoeopathic (Iron (Ferrous Phosphate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Comb Q Homoeopathic (Iron (Ferrous Phosphate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Comb Q Homoeopathic (Iron (Ferrous Phosphate)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in humans. Excessive dosages of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) may lead to accumulation of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in storage sites potentially leading to hemosiderosis. Do not administer Comb Q Homoeopathic (Iron (Ferrous Phosphate)) to patients with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (iron sucrose injection, USP), an Comb Q Homoeopathic (Iron (Ferrous Phosphate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (III)-hydroxide in sucrose for intravenous use. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) polymerization and m is the number of sucrose molecules associated with the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (III)-hydroxide.

Each mL contains 20 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) as Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose in water for injection. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is available in 10 mL single-use vials (200 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per 10 mL), 5 mL single-use vials (100 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Comb Q Homoeopathic ) is an aqueous complex of poly-nuclear Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (III)-hydroxide in sucrose. Following intravenous administration, Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is dissociated into Comb Q Homoeopathic (Iron (Ferrous Phosphate)) and sucrose and the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is dissociated into Comb Q Homoeopathic (Iron (Ferrous Phosphate)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose containing 100 mg of Comb Q Homoeopathic (Iron (Ferrous Phosphate)), three times weekly for three weeks, significant increases in serum Comb Q Homoeopathic (Iron (Ferrous Phosphate)) and serum ferritin and significant decreases in total Comb Q Homoeopathic (Iron (Ferrous Phosphate)) binding capacity occurred four weeks from the initiation of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Comb Q Homoeopathic ), its Comb Q Homoeopathic (Iron (Ferrous Phosphate)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Comb Q Homoeopathic (Iron (Ferrous Phosphate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Comb Q Homoeopathic (Iron (Ferrous Phosphate)) containing 100 mg of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency showed that a significant amount of the administered Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Comb Q Homoeopathic (Iron (Ferrous Phosphate)) trapping compartment.

Following intravenous administration of Comb Q Homoeopathic (Iron (Ferrous Phosphate)), Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose is dissociated into Comb Q Homoeopathic (Iron (Ferrous Phosphate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) containing 1,510 mg of sucrose and 100 mg of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Comb Q Homoeopathic (Iron (Ferrous Phosphate)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose containing 500 to 700 mg of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Comb Q Homoeopathic (Iron (Ferrous Phosphate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Comb Q Homoeopathic (Iron (Ferrous Phosphate)), the half-life of total serum Comb Q Homoeopathic (Iron (Ferrous Phosphate)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose.

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Comb Q Homoeopathic ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment and 24 in the historical control group) with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency anemia. Eligibility criteria for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Comb Q Homoeopathic (Iron (Ferrous Phosphate)), who were off intravenous Comb Q Homoeopathic (Iron (Ferrous Phosphate)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in 23 patients with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) deficiency and HDD-CKD who had been discontinued from Comb Q Homoeopathic (Iron (Ferrous Phosphate)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)). Exclusion criteria were similar to those in studies A and B. Comb Q Homoeopathic (Iron (Ferrous Phosphate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) versus Comb Q Homoeopathic (Iron (Ferrous Phosphate)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (325 mg ferrous sulfate three times daily for 56 days); or Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) group.

A statistically significantly greater proportion of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) subjects (35/79; 44.3%) compared to oral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Comb Q Homoeopathic (Iron (Ferrous Phosphate)) to patients with PDD-CKD receiving an erythropoietin alone without Comb Q Homoeopathic (Iron (Ferrous Phosphate)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Comb Q Homoeopathic (Iron (Ferrous Phosphate)) or Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Comb Q Homoeopathic (Iron (Ferrous Phosphate)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Comb Q Homoeopathic ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Comb Q Homoeopathic (Iron (Ferrous Phosphate)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Comb Q Homoeopathic (Iron (Ferrous Phosphate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Comb Q Homoeopathic (Iron (Ferrous Phosphate)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Comb Q Homoeopathic (Iron (Ferrous Phosphate)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Comb Q Homoeopathic ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)), each 5 mL vial contains 100 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)), and each 2.5 mL vial contains 50 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) (20 mg/mL).

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Comb Q Homoeopathic (Iron (Ferrous Phosphate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per mL, or undiluted (20 mg elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Comb Q Homoeopathic (Iron (Ferrous Phosphate)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Comb Q Homoeopathic (Iron (Ferrous Phosphate)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Comb Q Homoeopathic (Iron (Ferrous Phosphate)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Comb Q Homoeopathic (Iron (Ferrous Phosphate)) administration:

• Question patients regarding any prior history of reactions to parenteral Comb Q Homoeopathic (Iron (Ferrous Phosphate)) products
• Advise patients of the risks associated with Comb Q Homoeopathic (Iron (Ferrous Phosphate))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Comb Q Homoeopathic (Iron (Ferrous Phosphate)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Comb Q Homoeopathic (Iron (Ferrous Phosphate)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Comb Q Homoeopathic (Potassium Chloride) reviews

Comb Q Homoeopathic (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Comb Q Homoeopathic (Potassium Chloride) containing 1500 mg of microencapsulated Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) within the gastrointestinal tract is reduced.

Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Comb Q Homoeopathic (Potassium Chloride), and the structural formula is KCl. Comb Q Homoeopathic (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.

Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Comb Q Homoeopathic (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Comb Q Homoeopathic (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. Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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. Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Comb Q Homoeopathic (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 Comb Q Homoeopathic 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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of Comb Q Homoeopathic (Potassium Chloride).

Comb Q Homoeopathic (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 Comb Q Homoeopathic (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Comb Q Homoeopathic (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Comb Q Homoeopathic (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

Comb Q Homoeopathic (Potassium Chloride) 20 Meq

Potassium Sulfate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Comb Q Homoeopathic (Potassium Sulfate) reviews

Comb Q Homoeopathic (Potassium Sulfate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Comb Q Homoeopathic (Potassium Sulfate) chloride containing 1500 mg of microencapsulated Comb Q Homoeopathic (Potassium Sulfate) chloride, USP equivalent to 20 mEq of Comb Q Homoeopathic (Potassium Sulfate) in a tablet.

These formulations are intended to slow the release of Comb Q Homoeopathic (Potassium Sulfate) so that the likelihood of a high localized concentration of Comb Q Homoeopathic (Potassium Sulfate) chloride within the gastrointestinal tract is reduced.

Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Comb Q Homoeopathic (Potassium Sulfate) chloride, and the structural formula is KCl. Comb Q Homoeopathic (Potassium Sulfate) 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.

Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Comb Q Homoeopathic (Potassium Sulfate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) chloride.

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

CLINICAL PHARMACOLOGY

The Comb Q Homoeopathic (Potassium Sulfate) ion is the principal intracellular cation of most body tissues. Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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.

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

Comb Q Homoeopathic (Potassium Sulfate) depletion will occur whenever the rate of Comb Q Homoeopathic (Potassium Sulfate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Comb Q Homoeopathic (Potassium Sulfate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Comb Q Homoeopathic (Potassium Sulfate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Comb Q Homoeopathic (Potassium Sulfate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) in the form of high Comb Q Homoeopathic (Potassium Sulfate) food or Comb Q Homoeopathic (Potassium Sulfate) chloride may be able to restore normal Comb Q Homoeopathic (Potassium Sulfate) levels.

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

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Comb Q Homoeopathic (Potassium Sulfate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) salts may be indicated.

CONTRAINDICATIONS

Comb Q Homoeopathic (Potassium Sulfate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Comb Q Homoeopathic (Potassium Sulfate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Comb Q Homoeopathic (Potassium Sulfate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate), the administration of Comb Q Homoeopathic (Potassium Sulfate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Comb Q Homoeopathic (Potassium Sulfate) by the intravenous route but may also occur in patients given Comb Q Homoeopathic (Potassium Sulfate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Comb Q Homoeopathic (Potassium Sulfate) salts in patients with chronic renal disease, or any other condition which impairs Comb Q Homoeopathic (Potassium Sulfate) excretion, requires particularly careful monitoring of the serum Comb Q Homoeopathic (Potassium Sulfate) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) retention by inhibiting aldosterone production. Comb Q Homoeopathic (Potassium Sulfate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Comb Q Homoeopathic (Potassium Sulfate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Comb Q Homoeopathic (Potassium Sulfate) 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. Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Comb Q Homoeopathic (Potassium Sulfate) chloride and thus to minimize the possibility of a high local concentration of Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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. Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) salt such as Comb Q Homoeopathic (Potassium Sulfate) bicarbonate, Comb Q Homoeopathic (Potassium Sulfate) citrate, Comb Q Homoeopathic (Potassium Sulfate) acetate, or Comb Q Homoeopathic (Potassium Sulfate) gluconate.

PRECAUTIONS

General

The diagnosis of Comb Q Homoeopathic depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Comb Q Homoeopathic (Potassium Sulfate) depletion. In interpreting the serum Comb Q Homoeopathic (Potassium Sulfate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Comb Q Homoeopathic (Potassium Sulfate) while acute acidosis per se can increase the serum Comb Q Homoeopathic (Potassium Sulfate) concentration into the normal range even in the presence of a reduced total body Comb Q Homoeopathic (Potassium Sulfate). The treatment of Comb Q Homoeopathic (Potassium Sulfate) 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 (water) 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 Comb Q Homoeopathic (Potassium Sulfate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic 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 (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy Category C

Animal reproduction studies have not been conducted with Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Comb Q Homoeopathic (Potassium Sulfate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Comb Q Homoeopathic ion content of human milk is about 13 mEq per liter. Since oral Comb Q Homoeopathic (Potassium Sulfate) becomes part of the body Comb Q Homoeopathic (Potassium Sulfate) pool, so long as body Comb Q Homoeopathic (Potassium Sulfate) is not excessive, the contribution of Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) salts to persons with normal excretory mechanisms for Comb Q Homoeopathic (Potassium Sulfate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) by the average adult is 50 to 100 mEq per day. Comb Q Homoeopathic (Potassium Sulfate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Comb Q Homoeopathic (Potassium Sulfate) chloride.

Comb Q Homoeopathic (Potassium Sulfate) 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 Comb Q Homoeopathic (Potassium Sulfate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Comb Q Homoeopathic (Potassium Sulfate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Comb Q Homoeopathic (Potassium Sulfate) 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

Comb Q Homoeopathic (Potassium Sulfate) chloride 20 Meq

Sodium Chloride:

• 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
• Comb Q Homoeopathic (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

Comb Q Homoeopathic nitrite is indicated for sequential use with Comb Q Homoeopathic (Sodium Chloride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection is indicated for sequential use with Comb Q Homoeopathic (Sodium Chloride) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Comb Q Homoeopathic nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection and Comb Q Homoeopathic (Sodium Chloride) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Comb Q Homoeopathic (Sodium Chloride) thiosulfate, simultaneously with Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Comb Q Homoeopathic (Sodium Chloride) thiosulfate, with Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Comb Q Homoeopathic (Sodium Chloride) nitrite, followed by Comb Q Homoeopathic (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate.

Comb Q Homoeopathic (Sodium Chloride) nitrite injection and Comb Q Homoeopathic (Sodium Chloride) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Comb Q Homoeopathic (Sodium Chloride) nitrite should be administered first, followed immediately by Comb Q Homoeopathic (Sodium Chloride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Comb Q Homoeopathic (Sodium Chloride) nitrite should be reduced proportionately to the hemoglobin concentration.

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

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Comb Q Homoeopathic Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Comb Q Homoeopathic (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Comb Q Homoeopathic (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Comb Q Homoeopathic (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Comb Q Homoeopathic (Sodium Chloride) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Comb Q Homoeopathic (Sodium Chloride) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Comb Q Homoeopathic (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Comb Q Homoeopathic (Sodium Chloride) thiosulfate and Comb Q Homoeopathic (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection consists of:

• One vial of Comb Q Homoeopathic (Sodium Chloride) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Comb Q Homoeopathic nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Comb Q Homoeopathic (Sodium Chloride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Comb Q Homoeopathic (Sodium Chloride) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Comb Q Homoeopathic (Sodium Chloride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Comb Q Homoeopathic nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Comb Q Homoeopathic (Sodium Chloride) nitrite whenever possible. When Comb Q Homoeopathic (Sodium Chloride) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Comb Q Homoeopathic (Sodium Chloride) nitrite administered to an adult. Comb Q Homoeopathic (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Comb Q Homoeopathic (Sodium Chloride) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Comb Q Homoeopathic (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Comb Q Homoeopathic (Sodium Chloride) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Comb Q Homoeopathic (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Comb Q Homoeopathic nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Comb Q Homoeopathic (Sodium Chloride) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Comb Q Homoeopathic nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Comb Q Homoeopathic (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Comb Q Homoeopathic (Sodium Chloride) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Comb Q Homoeopathic (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Comb Q Homoeopathic (Sodium Chloride) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Comb Q Homoeopathic (Sodium Chloride) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Comb Q Homoeopathic nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Comb Q Homoeopathic (Sodium Chloride) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Comb Q Homoeopathic (Sodium Chloride) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Comb Q Homoeopathic (Sodium Chloride) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Comb Q Homoeopathic (Sodium Chloride) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Comb Q Homoeopathic (Sodium Chloride) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Comb Q Homoeopathic (Sodium Chloride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Comb Q Homoeopathic (Sodium Chloride) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Comb Q Homoeopathic (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Comb Q Homoeopathic (Sodium Chloride) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Comb Q Homoeopathic (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Comb Q Homoeopathic (Sodium Chloride) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Comb Q Homoeopathic nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Comb Q Homoeopathic (Sodium Chloride) nitrite is excreted in human milk. Because Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Comb Q Homoeopathic (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Comb Q Homoeopathic (Sodium Chloride) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Comb Q Homoeopathic nitrite in conjunction with Comb Q Homoeopathic (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Comb Q Homoeopathic (Sodium Chloride) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Comb Q Homoeopathic (Sodium Chloride) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Comb Q Homoeopathic (Sodium Chloride) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Comb Q Homoeopathic (Sodium Chloride) nitrite is known to be substantially excreted by the kidney, and the risk of adverse 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.

8.6 Renal Disease

Comb Q Homoeopathic (Sodium Chloride) nitrite 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.

10 OVERDOSAGE

Large doses of Comb Q Homoeopathic (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Comb Q Homoeopathic (Sodium Chloride) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Comb Q Homoeopathic (Sodium Chloride) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Comb Q Homoeopathic (Sodium Chloride) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Comb Q Homoeopathic (Sodium Chloride) nitrite has the chemical name nitrous acid Comb Q Homoeopathic (Sodium Chloride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Comb Q Homoeopathic (Sodium Chloride) Nitrite

Comb Q Homoeopathic (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Comb Q Homoeopathic (Sodium Chloride) nitrite injection.

Comb Q Homoeopathic (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Comb Q Homoeopathic (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Comb Q Homoeopathic (Sodium Chloride) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Comb Q Homoeopathic nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Comb Q Homoeopathic (Sodium Chloride) Nitrite

Comb Q Homoeopathic (Sodium Chloride) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Comb Q Homoeopathic (Sodium Chloride) nitrite. It has been suggested that Comb Q Homoeopathic (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Comb Q Homoeopathic (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Comb Q Homoeopathic (Sodium Chloride) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Comb Q Homoeopathic (Sodium Chloride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Comb Q Homoeopathic (Sodium Chloride) Nitrite

When 4 mg/kg Comb Q Homoeopathic (Sodium Chloride) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Comb Q Homoeopathic (Sodium Chloride) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Comb Q Homoeopathic (Sodium Chloride) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Comb Q Homoeopathic (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Comb Q Homoeopathic (Sodium Chloride) Nitrite

Comb Q Homoeopathic (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Comb Q Homoeopathic (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Comb Q Homoeopathic (Sodium Chloride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Comb Q Homoeopathic nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Comb Q Homoeopathic (Sodium Chloride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Comb Q Homoeopathic (Sodium Chloride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Comb Q Homoeopathic (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Comb Q Homoeopathic (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Comb Q Homoeopathic (Sodium Chloride) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Comb Q Homoeopathic (Sodium Chloride) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Comb Q Homoeopathic (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Comb Q Homoeopathic (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Comb Q Homoeopathic (Sodium Chloride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Comb Q Homoeopathic (Sodium Chloride) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Comb Q Homoeopathic (Sodium Chloride) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Comb Q Homoeopathic (Sodium Chloride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Comb Q Homoeopathic (Sodium Chloride) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Comb Q Homoeopathic (Sodium Chloride) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Comb Q Homoeopathic (Sodium Chloride) nitrite or 1 g/kg Comb Q Homoeopathic (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of Comb Q Homoeopathic (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Comb Q Homoeopathic (Sodium Chloride) nitrite and/or 0.5 g/kg Comb Q Homoeopathic (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Comb Q Homoeopathic (Sodium Chloride) cyanide required to cause death, and when administered together, Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Comb Q Homoeopathic (Sodium Chloride) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Comb Q Homoeopathic (Sodium Chloride) nitrite and Comb Q Homoeopathic (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Comb Q Homoeopathic (Sodium Chloride) nitrite, with or without Comb Q Homoeopathic (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Comb Q Homoeopathic (Sodium Chloride) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Comb Q Homoeopathic (Sodium Chloride) thiosulfate report its use in conjunction with Comb Q Homoeopathic (Sodium Chloride) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Comb Q Homoeopathic (Sodium Chloride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Comb Q Homoeopathic (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Comb Q Homoeopathic (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Comb Q Homoeopathic (Sodium Chloride) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Comb Q Homoeopathic (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Comb Q Homoeopathic Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Comb Q Homoeopathic (Sodium Chloride) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Comb Q Homoeopathic (Sodium Chloride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton