Zemplar Soft Capsules 1, 2 and 4 mcg

1. Name Of The Medicinal Product

Zemplar 1 microgram capsules, soft

Zemplar 2 micrograms capsules, soft

Zemplar 4 micrograms capsules, soft

2. Qualitative And Quantitative Composition

Each capsule, soft contains

	Paricalcitol	Excipients (Ethanol)
Zemplar 1 microgram	1 microgram	0.71 mg
Zemplar 2 micrograms	2 micrograms	1.42 mg
Zemplar 4 micrograms	4 micrograms	1.42 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsule, soft

1 microgram capsule: oval, gray soft capsule imprinted with

2 micrograms capsule: oval, orange-brown soft capsule imprinted with

4 micrograms capsule: oval, gold soft capsule imprinted with

4. Clinical Particulars

4.1 Therapeutic Indications

Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal insufficiency (chronic kidney disease Stages 3 and 4) patients and chronic renal failure (chronic kidney disease Stage 5) patients on haemodialysis or peritoneal dialysis.

4.2 Posology And Method Of Administration

Zemplar can be taken with or without food.

Chronic Kidney Disease (CKD) Stages 3 and 4

Zemplar should be administered once a day, either daily or three times a week taken every other day.

Initial Dose

The initial dose is based on baseline intact parathyroid hormone (iPTH) levels.

Table 1. Initial Dose
Baseline iPTH Level	Daily Dose	Three Times a Week Dose*
	1 microgram	2 micrograms
> 500 pg/mL (56 pmol/L)	2 micrograms	4 micrograms
* To be administered no more frequently than every other day

Dose Titration

Dosing must be individualised based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. Table 2 presents a suggested approach for dose titration.

Table 2. Dose Titration
iPTH Level Relative to Baseline	Dose Adjustment at 2 to 4 Week Intervals
Daily Dose	Three Times a Week Dose1
The same or increased	Increase 1 microgram	Increase 2 micrograms
Decreased by < 30%
Decreased by	Maintain	Maintain
Decreased > 60%	Decrease2 1 microgram	Decrease2 2 micrograms
iPTH < 60 pg/mL (7 pmol/L)
1 To be administered no more frequently than every other day. 2 If a patient is taking the lowest dose on the daily or three times a week regimen, and a dose reduction is needed, dosing frequency can be decreased.

Serum calcium levels should be closely monitored after initiation of the treatment and during dose titration periods. If hypercalcemia or a persistently elevated calcium-phosphorus product greater than 55 mg²/dL² (4.4 mmol² /L²) is observed, the dose of calcium based phosphate binders should be reduced or withheld. Alternatively, the dose of Zemplar may be reduced or temporarily interrupted. If interrupted, the drug should be restarted at a lower dose, when serum calcium and calcium-phosphorus product are in the target range.

Chronic Kidney Disease (CKD), Stage 5

Zemplar should be administered three times a week every other day.

Initial Dose

The initial dose of Zemplar in micrograms is based on a baseline iPTH level (pg/mL)/60 [(pmol/L)/7], up to an initial maximum dose of 32 micrograms.

Dose Titration

Subsequent dosing should be individualised and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of paricalcitol capsules is based on the following formula:

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium or elevated Ca x P is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder.

If serum calcium > 11.0 mg/dL (2.8 mmol/L) or Ca x P > 70 mg²/dL² (5.6 mmol²/L²) or iPTH

As iPTH approaches the target range (150-300 pg/mL), small, individualised dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio may be warranted.

Special Populations

Hepatic Impairment:

No dose adjustment is required in patients with mild to moderate hepatic impairment.

There is no experience in patients with severe hepatic impairment (see Section 5.2).

Paediatric population:

Safety and efficacy of Zemplar Capsules in paediatric patients have not been established (see Section 5.1).

Elderly:

No overall differences in safety and effectiveness were observed between elderly patients (65 – 75 years) with regard to younger patients, but greater sensitivity of some older individuals cannot be ruled out.

4.3 Contraindications

Paricalcitol should not be given to patients with evidence of vitamin D toxicity, hypercalcaemia, or hypersensitivity to paricalcitol or any of the excipients in this medicinal product.

4.4 Special Warnings And Precautions For Use

Over suppression of parathyroid hormone may result in elevations of serum calcium levels and may lead to low-turnover bone disease. Patient monitoring and individualised dose titration is required to reach appropriate physiological endpoints.

If clinically significant hypercalcaemia develops and the patient is receiving a calcium-based phosphate binder, the dose of the calcium-based phosphate binder should be reduced or interrupted.

Chronic hypercalcaemia may be associated with generalized vascular calcification and other soft-tissue calcification.

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol (see Section 4.5).

Caution should be exercised if co-administering paricalcitol with ketoconazole (see Section 4.5).

Warning for excipients:

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 1 mcg, 2 mcg and 4 mcg capsule which may be harmful to those suffering from alcoholism (refer to sections 2 and 4.2). To be taken into account in pregnant or breast-feeding women, children and high risk groups such as patients with liver disease or epilepsy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ketoconazole: Ketoconazole is known to be a nonspecific inhibitor of several cytochrome P450 enzymes. The available in vivo and in vitro data suggest that ketoconazole may interact with enzymes that are responsible for the metabolism of paricalcitol and other vitamin D analogs. Caution should be taken while dosing paricalcitol with ketoconazole.The effect of multiple doses of ketaconazole administered as 200 mg, twice daily (BID) for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-

Specific interaction studies were not performed. Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol.

Phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol due to an increased risk of hypercalcaemia and Ca x P product elevation.

High doses of calcium-containing preparation or thiazide diuretics may increase the risk of hypercalcaemia.

Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with vitamin D preparations, because hypermagnesemia may occur.

Aluminium-containing preparations (e.g. antacids, phosphate-binders) should not be administered chronically with Vitamin D medicinal products, as increased blood levels of aluminium and aluminium bone toxicity may occur.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.

4.6 Pregnancy And Lactation

There is no adequate data on the use of paricalcitol in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Potential risk in human use is not known, therefore paricalcitol should be not be used unless clearly necessary.

Lactation: It is not known whether paricalcitol is excreted in human milk. Animal studies have shown excretion of paricalcitol or its metabolites in breast milk, in small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Zemplar should be made taking into account the benefit of breast-feeding to the child and the benefit of Zemplar therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive or use machines have been performed, however, paricalcitol is expected to have negligible effect on the ability to drive or use machines.

4.8 Undesirable Effects

Chronic Kidney Disease, Stages 3 and 4

The safety of paricalcitol capsules has been evaluated in three 24-week, double-blind, placebo-controlled, multi-centre clinical trials involving 220 CKD Stage 3 and 4 patients. There were no statistically significant differences between the paricalcitol-treated patients and placebo-treated patients in the incidence of hypercalcaemia Zemplar (2/106, 2 %) vs placebo (0/111, 0 %) or elevated calcium phosphorus product Zemplar (13/106, 12%) vs placebo (7/111, 6%).

The most commonly reported adverse reaction for paricalcitol treated patients was rash, occurring in 2% of patients.

All adverse events at least possibly related to paricalcitol, both clinical and laboratory, are displayed in Table 3 by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: very common (

Table 3. Adverse Reactions Reported in Stages 3 & 4 CKD Clinical Studies

System Organ Class	Preferred Term	Frequency
Investigations	Hepatic Enzyme Abnormal	Uncommon
Nervous system disorders	Dizziness Dysgeusia	Uncommon Uncommon
Gastrointestinal disorders	Stomach discomfort Constipation Dry mouth	Common Uncommon Uncommon
Skin and subcutaneous tissue disorders	Rash Pruritus Urticaria	Common Uncommon Uncommon
Musculoskeletal and connective tissue disorders	Muscle spasms	Uncommon
Immune system disorders	Hypersensitivity	Uncommon

Chronic Kidney Disease, Stage 5

The safety of paricalcitol capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multi-centre clinical trial involving 88 CKD Stage 5 patients. There were no statistically significant differences between the paricalcitol-treated patients and placebo-treated patients in the incidence of hypercalcaemia Zemplar (1/61, 2%) vs placebo (0/26, 0.0%), or elevated calcium phosphorus product Zemplar (6/61, 10%) vs placebo (1/26, 4%).

All adverse events at least possibly related to paricalcitol, both clinical and laboratory, are displayed in Table 4 by MedDRA System Organ Class, Preferred Term and frequency. The following frequency groupings are used: very common (

Table 4. Adverse Reactions Reported in Stage 5 CKD pivotal phase III Study

System Organ Class	Preferred Term	Frequency
Nervous system disorders	Dizziness	Common
Gastrointestinal disorders	Diarrhoea Gastroesophageal reflux disease	Common Common
Skin and subcutaneous tissue disorders	Acne	Common
Metabolism and nutrition disorders	Hypercalcaemia Hypocalcaemia Decreased appetite	Common Common Common
Reproductive system and breast disorders	Breast tenderness	Common

The following adverse reactions have been seen in clinical trials and in post-marketing with Zemplar injection.

System Organ Class	Preferred Term	Frequency
Investigations	Bleeding time prolonged, aspartate aminotransferase increased, laboratory test abnormal, weight decreased	Uncommon
Cardiac disorders	Cardiac arrest, arrhythmia, atrial flutter	Uncommon
Blood and lymphatic system disorders	Anaemia, leukopenia, lymphadenopathy	Uncommon
Nervous system disorders	Headache, dysgeusia	Common
Coma,cerebrovascular accident, transient ischemic attack, syncope, myoclonus, hypoaesthesia, paraesthesia, dizziness	Uncommon
Eye disorders	Glaucoma, conjunctivitis	Uncommon
Ear and labyrinth disorders	Ear disorder	Uncommon
Respiratory, thoracic and mediastinal disorders	Pulmonary oedema, asthma, dyspnoea, epistaxis, cough	Uncommon
Gastrointestinal disorders	Rectal haemhorrhage, colitis, diarrhoea, gastritis, dyspepsia, dysphagia, abdominal pain, constipation, nausea, vomiting, dry mouth, gastrointestinal disorder	Uncommon
Gastrointestinal haemorrhage	unknown
Skin and subcutaneous tissue disorders	Pruritus	Common
Bullous dermatitis, alopecia, hirsutism, rash, hyperhidrosis	Uncommon
Musculoskeletal and connective tissue disorders	Arthralgia, joint stiffness, back pain, muscle twitching, myalgia	Uncommon
Endocrine Disorders	Hypoparathyrodism	Common
Hyperparathyrodism	Uncommon
Metabolism and nutrition disorders	Hypercalcaemia, Hyperphosphataemia	Common
Hyperkalaemia, hypocalcemia, anorexia,	Uncommon
Infections and infestations	Sepsis, pneumonia, infection , pharyngitis, vaginal infection, influenza	Uncommon
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Breast cancer	Uncommon
Vascular disorders	Hypertension, hypotension	Uncommon
General disorders and administration site conditions	Gait disturbance, oedema, peripheral oedema, pain, injection site pain, pyrexia, chest pain, condition aggravated, asthenia, malaise, thirst	Uncommon
Immune system disorders	Hypersensitivity	Uncommon
Laryngeal oedema, angioedema, urticaria	Not Known
Reproductive system and breast disorders	Breast pain, erectile dysfunction	Uncommon
Psychiatric disorders	Confusional state, delirium, depersonalization, agitation, insomnia, nervousness	Uncommon

4.9 Overdose

Excessive administration of Zemplar capsules can cause hypercalcaemia, hypercalciuria, hyperphosphataemia, and over suppression of parathyroid hormone. High intake of calcium and phosphate concomitant with Zemplar capsules may lead to similar abnormalities.

Treatment of patients with clinically significant hypercalcaemia consists of immediate dose reduction or interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilisation, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), and haemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted.

Signs and symptoms of vitamin D intoxication associated with hypercalcaemia include:

Early: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

Late: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, pruritis, hyperthermia, decreased libido, elevated BUN, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, hypertension, cardiad arrhythmias, somnolence, death and rarely, overt psychosis.

Serum calcium levels should be monitored frequently until normocalcaemia ensues.

Paricalcitol is not significantly removed by dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-parathyroid agents–ATC code: H05BX02.

Mechanism of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D₂) and the A (19-nor) ring. Unlike calcitriol, paricalcitol is a selective vitamin D receptor (VDR) activator. Paricalcitol selectively upregulates the VDR in the parathyroid glands without increasing VDR in the intestine and is less active on bone resorption. Paricalcitol also upregulates the calcium sensing receptor in the parathyroid glands. As a result, paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and decreasing PTH synthesis and secretion, with minimal impact on calcium and phosphorus levels, and can act directly on bone cells to maintain bone volume and improve mineralization surfaces. Correcting abnormal PTH levels, with normalisation of calcium and phosphorus homeostasis, may prevent or treat the metabolic bone disease associated with chronic kidney disease.

Clinical Efficacy

Chronic Kidney Disease, Stages 3-4

The primary efficacy endpoint of at least two consecutive

Chronic kidney disease, Stage 5

The primary efficacy endpoint of at least two consecutive

Paediatric clinical data with Zemplar Injection (IV)

The safety and effectiveness of Zemplar IV were examined in a 12-week randomised, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis. The six youngest Zemplar IV-treated patients in the study were 5 - 12 years old. The initial dose of Zemplar IV was 0.04 mcg/kg 3 times per week, based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week based on baseline iPTH level of

5.2 Pharmacokinetic Properties

Absorption

Paricalcitol is well absorbed. In healthy subjects, following oral administration of paricalcitol at 0.24 micrograms/kg, the mean absolute bioavailability was approximately 72%; the maximum plasma concentration (C_max) was 0.630 ng/mL (1.512 pmol/mL) at 3 hours and area under the concentration time curve (AUC_0-) was 5.25 ng•h/mL (12.60 pmol•h/mL). The mean absolute bioavailability of paricalcitol in hemodialysis (HD) and peritoneal dialysis (PD) patients is 79% and 86%, respectively, with the upper bound of 95% confidence interval of 93% and 112%, respectively. A food interaction study in healthy subjects indicated that the C_max and AUC_0- were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Therefore, Zemplar Capsules may be taken without regard to food.

The C_max and AUC_0- of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 micrograms/kg in healthy subjects. Following multiple dosing, either as daily or three times a week in healthy subjects, steady-state exposure was reached within seven days.

Distribution

Paricalcitol is extensively bound to plasma proteins (> 99%). The ratio of blood paricalcitol to plasma paricalcitol concentration averaged 0.54 over the concentration range of 0.01 to 10 ng/mL (0.024 to 24 pmol/mL) indicating that very little drug associated with blood cells. The mean apparent volume of distribution following a 0.24 micrograms/kg dose of paricalcitol in healthy subjects was 34 litres.

Metabolism and Excretion

After oral administration of a 0.48 micrograms/kg dose of ³H-paricalcitol, parent drug was extensively metabolised, with only about 2% of the dose eliminated unchanged in the faeces, and no parent drug found in the urine. Approximately 70% of the radioactivity was eliminated in the faeces and 18% was recovered in the urine. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolised by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation.

Elimination

In healthy subjects, the mean elimination half-life of paricalcitol is five to seven hours over the studied dose range of 0.06 to 0.48 micrograms/kg. The degree of accumulation was consistent with the half-life and dosing frequency. Haemodialysis procedure has essentially no effect on paricalcitol elimination.

Special Populations

Elderly

The pharmacokinetics of paricalcitol have not been investigated in patients greater than 65 years.

Paediatric

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

Gender

The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 micrograms/kg dose range were gender independent.

Hepatic Impairment

In a study performed with Zemplar intravenous, the disposition of paricalcitol (0.24 micrograms/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (in accordance with the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol was similar across the range of hepatic function evaluated in this study. No dosing adjustment is required in patients with mild to moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

Paricalcitol pharmacokinetics following single dose administration were characterised in patients with CKD Stage 3 or moderate renal impairment (n = 15, GFR = 36.9 to 59.1 mL/min/1.73 m²), CKD Stage 4 or severe renal impairment (n = 14, GFR = 13.1 to 29.4 mL/min/1.73 m²), and CKD 5 or end-stage renal disease [n = 14 in haemodialysis (HD) and n = 8 in peritoneal dialysis (PD)]. Similar to endogenous 1,25(OH)₂ D₃, the pharmacokinetics of paricalcitol following oral administration were affected significantly by renal impairment, as shown in Table 5. Compared to healthy subjects results obtained, Chronic Kidney Disease, Stage 3, 4, and 5 patients showed decreased CL/F and increased half-life.

Table 5. Comparison of Mean ± SD Pharmacokinetic Parameters in Different Stages of Renal Impairment versus Healthy Subjects

Pharmacokinetic Parameter	Healthy Subjects	CKD Stage 3	CKD Stage 4	CKD Stage 5
HD	PD
n	25	15	14	14	8
Dose (micrograms/kg)	0.240	0.047	0.036	0.240	0.240
CL/F(L/h)	3.6 ± 1.0	1.8 ± 0.5	1.5 ± 0.4	1.8 ± 0.8	1.8 ± 0.8
t½ (h)	5.9 ± 2.8	16.8 ± 2.6	19.7 ± 7.2	13.9 ± 5.1	17.7 ± 9.6
fu* (%)	0.06 ± 0.01	0.06 ± 0.01	0.07 ± 0.02	0.09 ± 0.04	0.13 ± 0.08
* Measured at 15 nM paricalcitol concentration.

Following oral administration of paricalcitol capsules, the pharmacokinetic profile of paricalcitol for Chronic kidney disease, Stages 3 to 5 was comparable. Therefore, no special dosing adjustments are required other than those recommended (see section 4.2).

5.3 Preclinical Safety Data

Salient findings in the repeat-dose toxicology studies in rodents and dogs were generally attributed to paricalcitol's calcaemic activity. Effects not clearly related to hypercalcaemia included decreased white blood cell counts and thymic atrophy in dogs, and altered APTT values (increased in dogs, decreased in rats). WBC changes were not observed in clinical trials of paricalcitol.

Paricalcitol did not affect fertility in rats and there was no evidence of teratogenic activity in rats or rabbits. High doses of other vitamin D preparations applied during pregnancy in animals lead to teratogenesis. Paricalcitol was shown to affect fetal viability, as well as to promote a significant increase of peri-natal and post-natal mortality of newborn rats, when administered at maternally toxic doses.

Paricalcitol did not exhibit genotoxic potential in a set of in-vitro and in-vivo genotoxicity assays.

Carcinogenicity studies in rodents did not indicate any special risks for human use.

Doses administered and/or systemic exposures to paricalcitol were slightly higher than therapeutic doses/systemic exposures.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule contents:

Medium chain triglycerides

Ethanol

Butylhydroxytoluene

Capsule shell:

1 microgram	2 microgram	4 microgram
Gelatin	Gelatin	Gelatin
Glycerol	Glycerol	Glycerol
Water	Water	Water
Titanium dioxide (E171)	Titanium dioxide (E171)	Titanium dioxide (E171)
Iron oxide black (E172)	Iron oxide black (E172)	Iron oxide black (E172)
	Iron oxide yellow (E172)

Black Ink:

Propylene glycol

Black iron oxide (E172)

Polyvinyl acetate phthalate

Polyethylene glycol 400

Ammonium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

High-density polyethylene (HDPE) bottles closed with polypropylene caps. Each bottle contains 30 capsules.

PVC/fluoropolymer/aluminium blister packs containing 7 or 28 capsules. Each carton contains 1 or 4 blisters. Each blister foil card contains 7 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Abbott Laboratories Limited,

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

8. Marketing Authorisation Number(S)

Zemplar 1 microgram capsules, soft: PL 00037/0626

Zemplar 2 micrograms capsules, soft: PL 00037/0627

Zemplar 4 micrograms capsules, soft: PL 00037/0628

9. Date Of First Authorisation/Renewal Of The Authorisation

6 December 2007

Trisenox 1 mg / ml concentrate for solution for infusion

1. Name Of The Medicinal Product

TRISENOX 1 mg/ml, concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One ml of TRISENOX contains 1 mg of Arsenic trioxide

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Concentrate for solution for infusion

Sterile, clear, colourless, aqueous solution.

4. Clinical Particulars

4.1 Therapeutic Indications

TRISENOX is indicated for induction of remission and consolidation in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene. Previous treatment should have included a retinoid and chemotherapy.

The response rate of other acute myelogenous leukaemia subtypes to TRISENOX has not been examined.

4.2 Posology And Method Of Administration

Posology

TRISENOX must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and the special monitoring procedures described in Section 4.4 must be followed. The same dose is recommended for children, adults, and elderly.

Induction treatment schedule: TRISENOX must be administered intravenously at a fixed dose of 0.15 mg/kg/day given daily until the bone marrow remission is achieved (less than 5% blasts present in cellular bone marrow with no evidence of leukaemic cells). If bone marrow remission has not occurred by day 50, dosing must be discontinued.

Consolidation schedule: Consolidation treatment must begin 3 to 4 weeks after completion of induction therapy. TRISENOX is to be administered intravenously at a dose of 0.15 mg/kg/day for 25 doses given 5 days per week, followed by 2 days interruption, repeated for 5 weeks.

Paediatric use: The experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treated with TRISENOX at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a complete response. Safety and effectiveness in paediatric patients under 5 years of age have not been studied.

Patients with hepatic and/or renal impairment:

Since limited data are available across all hepatic impairment groups and across all renal impairment groups, caution is advised in the use of TRISENOX in patients with hepatic and/or renal impairment.

Method of administration

TRISENOX must be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required. Patients must be hospitalised at the beginning of treatment due to symptoms of disease and to ensure adequate monitoring.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special Warnings And Precautions For Use

Clinically unstable APL patients are especially at risk and will require more frequent monitoring of electrolyte and glycaemia levels as well as more frequent haematologic, hepatic, renal and coagulation parameter tests.

Leukocyte Activation Syndrome (APL Differentiation Syndrome): Twenty-five percent of patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously twice a day) must be immediately initiated, irrespective of the leukocyte count and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome. It is recommended that chemotherapy not be added to treatment with steroids since there is no experience with administration of both steroids and chemotherapy during treatment of the leukocyte activation syndrome due to TRISENOX. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancy. Monitoring and management for these patients should be as described above.

Electrocardiogram (ECG) Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. Previous treatment with anthracyclines may increase the risk of QT prolongation. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products (such as class Ia and III antiarrythmics (e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), some macrolides (e.g. erythromycin), some antihistamines (e.g. terfenadine and astemizole), some quinolone antibiotics (e.g. sparfloxacin), and other individual drugs known to increase QT interval (e.g. cisapride)), a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, amphotericin B or other conditions that result in hypokalemia or hypomagnesaemia. In clinical trials, 40% of patients treated with TRISENOX experienced at least one QT corrected (QTc) interval prolongation greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned to baseline by the end of 8 weeks after TRISENOX infusion. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.

ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG must be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; preexisting electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations must be kept above 4 mEq/l and magnesium concentrations must be kept above 1.8 mg/dl. Patients who reach an absolute QT interval value> 500 msec must be reassessed and immediate action must be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, TRISENOX therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion. Electrocardiograms must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Dose Modification: Treatment with TRISENOX must be interrupted, adjusted, or discontinued before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria, Version 2 is observed and judged to be possibly related to TRISENOX treatment. Patients who experience such reactions that are considered TRISENOX related must resume treatment only after resolution of the toxic event or after recovery to baseline status of the abnormality that prompted the interruption. In such cases, treatment must resume at 50% of the preceding daily dose. If the toxic event does not recur within 3 days of restarting treatment at the reduced dose, the daily dose can be escalated back to 100% of the original dose. Patients who experience a recurrence of toxicity must be removed from treatment.

Laboratory tests: The patient's electrolyte and glycaemia levels, as well as haematologic, hepatic, renal and coagulation parameter tests must be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

Patients with renal impairment:

Since limited data are available across all renal impairment groups, caution is advised in the use of TRISENOX in patients with renal impairment. The experience in patients with severe renal impairment is insufficient to determine if dose adjustment is required.

The use of TRISENOX in patients on dialysis has not been studied.

Patients with hepatic impairment:

Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. The experience in patients with severe hepatic impairment is insufficient to determine if dose adjustment is required.

Elderly patients: There is limited clinical data on the use of TRISENOX in the elderly population. Caution is needed in these patients.

Hyperleukocytosis: Treatment with TRISENOX has been associated with the development of hyperleukocytosis (³/μl) in some patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleukocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleukocytosis was never treated with additional chemotherapy and resolved on continuation of TRISENOX. WBC counts during consolidation were not as high as during induction treatment and were < 10 x 10³/μl, except in one patient who had a WBC count of 22 x 10³/μl during consolidation. Twenty patients (50%) experienced leukocytosis; however, in all these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leukopheresis was not required.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal assessments of pharmacokinetic interactions between TRISENOX and other therapeutic medicinal products have been conducted. QT/QTc prolongation is expected during treatment with TRISENOX, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalemia or hypomagnesaemia, such as diuretics or amphotericin B, may be at higher risk for torsade de pointes. Caution is advised when TRISENOX is coadministered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents, is provided in Section 4.4. The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

4.6 Pregnancy And Lactation

Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies (see 5.3). There are no studies in pregnant women using TRISENOX. If this medicinal product is used during pregnancy or if the patient becomes pregnant while taking this product, the patient must be informed of the potential harm to the foetus. Men, and women of childbearing potential must use effective contraception during treatment with TRISENOX.

Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, breastfeeding must be discontinued prior to and throughout administration.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Related adverse reactions of CTC grade 3 and 4 occurred in 37% of patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leukocytosis occurred in 50% of patients with APL, as determined by haematology assessments, rather than adverse event reports.

Serious adverse reactions were common (1-10%) and not unexpected in this population. Those serious adverse reactions attributed to TRISENOX included APL differentiation syndrome (3), leukocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to haemorrhage, infections, pain, diarrhoea, nausea.

In general, treatment

The table below lists the related grade 3 and 4 adverse drug reactions for the 107 patients treated with TRISENOX in clinical trials (frequencies defined as: common

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Common	Uncommon
Blood and lymphatic system disorders	Neutropenia Thrombocytopenia	Febrile neutropenia Leucocytosis Leucopenia
Metabolism and nutrition disorders	Hyperglycaemia Hypokalaemia	Hypermagnesaemia Hypernatraemia Ketoacidosis
Nervous system disorders	Paraesthesia
Cardiac disorders		Pericardial effusion Tachycardia
Vascular disorders		Vasculitis
Respiratory, thoracic and mediastinal disorders	Pleuritic pain Dyspnoea	Pulmonary alveolar haemorrhage Pleural effusion Hypoxia
Gastrointestinal disorders		Diarrhoea
Skin and subcutaneous tissue disorders		Pruritus Erythema
Musculoskeletal and connective tissue disorders	Bone pain Arthralgia	Myalgia
General disorders and administration site conditions	Pyrexia Fatigue	Chest pain Pain
Investigations	ECG QT prolonged ALT increased Aspartate amino transferase increased	Hyperbilirubinaemia Hypomagnesaemia

During TRISENOX treatment, 13 of the 52 patients in the APL studies had one or more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis (see Section 4.4). Twenty-seven patients had leukocytosis (WBC ³/μl) during induction, 4 of whom had values above 100,000/μl. Baseline white blood cell (WBC) counts did not correlate with development of leukocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leukocytosis was not treated with chemotherapeutic medicinal products. Medicinal products that are used to lower the white blood cell count often exacerbate the toxicities associated with leukocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leukocytosis, following treatment with chemotherapeutic medicinal products to lower WBC count. Observation is the recommended approach with intervention only in selected cases.

Mortality in the pivotal studies from disseminated intravascular coagulation (DIC) associated haemorrhage was very common (> 10%), which is consistent with the early mortality reported in the literature.

Arsenic trioxide can cause QT interval prolongation (see Section 4.4). QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. She went onto consolidation without further evidence of QT prolongation.

Peripheral neuropathy, characterised by paresthesia/dysesthesia, is a common and well known effect of environmental arsenic. Only 2 patients discontinued treatment early due to this adverse event and one went on to receive additional TRISENOX on a subsequent protocol. Forty-four percent of patients experienced symptoms that could be associated with neuropathy; most were mild to moderate and were reversible upon cessation of treatment with TRISENOX.

The following adverse events have been identified during the post-approval use of TRISENOX and have been included following consideration of the observed frequency, seriousness and possible causal relationship to TRISENOX. They are listed below by system organ class and frequency (frequencies are defined as: uncommon (

System Organ Class	Uncommon	Not known
Infection and Infestations	Sepsis Pneumonia Herpes zoster
Blood and Lymphatics System Disorders	Anaemia	Pancytopenia
Metabolism and Nutrition Disorders	Dehydration Fluid retention
Psychiatric Disorders	Confusional state
Nervous System Disorders	Convulsions Dizziness
Eye Disorders	Vision blurred
Cardiac Disorders	Cardiac failure Ventricular tachycardia Ventricular extrasystoles
Vascular Disorders	Hypotension
Respiratory, Thoracic and Mediastinal Disorders	Pneumonitis	Differentiation syndrome
Gastrointestinal Disorders	Vomiting Abdominal pain
Skin and Subcutaneous Disorders	Face oedema Rash
Renal and Urinary Disorders	Renal failure
General Disorders and Administration Site Conditions	Oedema Chills
Investigations	Blood creatinine increased Weight increased

In post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also been reported for the treatment of malignancies other than APL with TRISENOX.

4.9 Overdose

If symptoms suggestive of serious acute arsenic toxicity (e.g. convulsions, muscle weakness and confusion) appear, TRISENOX must be immediately discontinued and chelating therapy with penicilamine at a daily dose ² every 8 hours during 5 days and then every 12 hours during 2 weeks is recommended. For patients with severe, acute arsenic overdose, dialysis should be considered

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27

Mechanism of action: The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein Pro-Myelocytic Leukaemia/Retinoic Acid Receptor-alpha (PML/RAR alpha).

Clinical trials: TRISENOX has been investigated in 52 APL patients, previously treated with an anthracycline and a retinoid regimen, in two open-label, single-arm, non-comparative studies. One was a single investigator clinical study (n=12) and the other was a multicentre, 9-institution study (n=40). Patients in the first study received a median dose of 0.16 mg/kg/day of TRISENOX (range 0.06 to 0.20 mg/kg/day) and patients in the multicentre study received a fixed dose of 0.15 mg/kg/day. TRISENOX was administered intravenously over 1 to 2 hours until the bone marrow was free of leukaemic cells, up to a maximum of 60 days. Patients with complete remission received consolidation therapy with TRISENOX for 25 additional doses over a 5 week period. Consolidation therapy began 6 weeks (range, 3-8) after induction in the single institution study and 4 weeks (range, 3-6) in the multicentre study. Complete remission (CR) was defined as the absence of visible leukaemic cells in the bone marrow and peripheral recovery of platelets and white blood cells.

Patients in the single centre study had relapsed following 1-6 prior therapy regimens and 2 patients had relapsed following stem cell transplantation. Patients in the multicentre study had relapsed following 1-4 prior therapy regimens and 5 patients had relapsed following stem cell transplantation. The median age in the single centre study was 33 years (age range 9 to 75). The median age in the multicentre study was 40 years (age range 5 to 73).

The results are summarised in the table below.

	Single Centre Trial N=12	Multicentre Trial N=40
TRISENOX Dose, mg/kg/day (Median, Range)	0.16 (0.06 – 0.20)	0.15
Complete Remission	11 (92%)	34 (85%)
Time to Bone Marrow Remission (Median)	32 days	35 days
Time to CR (Median)	54 days	59 days
18-Month Survival	67%	66%

The single institution study included 2 paediatric patients (< 18 years old), both of whom achieved CR. The multicentre trial included 5 paediatric patients (< 18 years old), 3 of whom achieved CR. No children of less than 5 years of age were treated.

In a follow-up treatment after consolidation, 7 patients in the single institution study and 18 patients in the multicentre study received further maintenance therapy with TRISENOX. Three patients from the single institution study and 15 patients from the multicentre study had stem cell transplants after completing TRISENOX. The Kaplan-Meier median CR duration for the single institution study is 14 months and has not been reached for the multicentre study. At last follow-up, 6 of 12 patients in the single institution study were alive with a median follow-up time of 28 months (range 25 to 29). In the multicentre study 27 of 40 patients were alive with a median follow-up time of 16 months (range 9 to 25). Kaplan-Meier estimates of 18-month survival for each study are shown below.

Cytogenetic confirmation of conversion to a normal genotype and Reverse Transcriptase - Polymerase Chain Reaction (RT-PCR) detection of PML/RARα conversion to normal are shown in the table below.

Cytogenetics after TRISENOX therapy

	Single Centre Pilot Trial N with CR = 11	Multicentre Trial N with CR = 34
Conventional Cytogenetics [t(15;17)] Absent Present Not evaluable	8 (73%) 1 (9%) 2 (18%)	31 (91%) 0% 3 (9%)
RT-PCR for PML/ RARα   Negative Positive Not evaluable	8 (73%) 3 (27%) 0	27 (79%) 4 (12%) 3 (9%)

Responses were seen across all age groups tested, ranging from 6 to 75 years. The response rate was similar for both genders. There is no experience on the effect of TRISENOX on the variant APL containing the t(11;17) and t(5;17) chromosomal translocations.

5.2 Pharmacokinetic Properties

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As^III). As^III is the pharmacologically active species of arsenic trioxide.

In the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. The decline from peak plasma concentration of As^III occurs in a biphasic manner and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, an approximate 2-fold accumulation of As^III was observed as compared to a single infusion. This accumulation was slightly more than expected based on single-dose results.

Distribution:

The volume of distribution (V_d) for As^III is large (>400 L) indicating significant distribution into the tissues with negligible protein binding. V_d is also weight dependent, increasing with increasing body weight. Total arsenic accumulates mainly in the liver, kidney, and heart and, to a lesser extent, in the lung, hair, and nails.

Metabolism:

The metabolism of arsenic trioxide involves oxidation of arsenious acid (As^III), the active species of arsenic trioxide, to arsenic acid (As^V), as well as oxidative methylation to monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V) by methyltransferases, primarily in the liver. The pentavalent metabolites, MMA^V and DMA^V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but due to their longer half-life, accumulate more upon multiple dosing than does As^III. The extent of accumulation of these metabolites is dependent on the dosing regimen. Approximate accumulation ranged from 1.4- to 8-fold following multiple as compared to single dose administration. As^V is present in plasma only at relatively low levels.

In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11. Drugs that are substrates for these P450 enzymes are not expected to interact with TRISENOX.

Elimination:

Approximately 15% of the administered TRISENOX dose is excreted in the urine as unchanged As^III. The methylated metabolites of As^III (MMA^V, DMA^V) are primarily excreted in the urine. The plasma concentration of As^III declines from peak plasma concentration in a biphasic manner with a mean terminal elimination half-life of 10 to 14 hours. The total clearance of As^III over the single^V and DMA^V are 32 hours and 70 hours, respectively.

Renal Impairment:

Plasma clearance of As^III was not altered in patients with mild renal impairment (creatinine clearance of 50-80 mL/min) or moderate renal impairment (creatinine clearance of 30-49 mL/min). The plasma clearance of As^III in patients with severe renal impairment (creatinine clearance less than 30 mL/min) was 40% lower when compared with patients with normal renal function (see section 4.4).

Systemic exposure to MMA^V and DMA^V tended to be larger in patients with renal impairment; the clinical consequence of this is unknown but no increased toxicity was noted.

Hepatic Impairment:

Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepatic impairment indicate that As^III or As^V do not accumulate following twice-weekly infusions. No clear trend toward an increase in systemic exposure to As^III, As^V, MMA^V or DMA^V was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC.

5.3 Preclinical Safety Data

Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity and teratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10 times the recommended clinical dose (mg/m2). Fertility studies have not been conducted with TRISENOX. Arsenic compounds induce chromosomal aberrations and morphological transformations of mammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic trioxide have been performed. However, arsenic trioxide and other inorganic arsenic compounds are recognised as human carcinogens.

6. Pharmaceutical Particulars

6.1 List Of Excipients

sodium hydroxide

hydrochloric acid as pH adjuster

water for injections

6.2 Incompatibilities

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.

6.3 Shelf Life

4 years.

After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 15-30°C and 48 hours at refrigerated (2-8°C) temperatures. From a microbiological point of view, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not freeze.

6.5 Nature And Contents Of Container

Type I borosilicate glass ampoule of 10 ml. Each pack contains 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Preparation of TRISENOX

ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF TRISENOX SINCE NO PRESERVATIVE IS PRESENT.

TRISENOX must be diluted with 100 to 250 ml of glucose 50 mg/ml (5%) injection or sodium chloride 9 mg/ml (0.9%) injection immediately after withdrawal from the ampoule. For single use only. Unused portions of each ampoule must be discarded properly. Do not save any unused portions for later administration.

TRISENOX must not be mixed with or concomitantly administered in the same intravenous line with other medicinal products.

TRISENOX must be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required.

The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration. Do not use the preparation if foreign particulate matter is present.

Procedure for proper disposal

Any unused product, any items that come into contact with the product, and waste material must be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Cephalon Europe

5 Rue Charles Martigny

94700 Maisons Alfort

FRANCE

8. Marketing Authorisation Number(S)

EU/1/02/204/001

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 05 March 2002

Date of last renewal: 05 March 2007

10. Date Of Revision Of The Text

August 2010

Quick Cure

Dosage Form: FOR ANIMAL USE ONLY
Fresh and Saltwater Fish Medication for the Fast Relief of Ick and Protozoan Parasites

DIRECTIONS

Effectively Treats Ick, Mild Fluke Outbreaks, Gasping for Air, Flicking Against Rocks, Protozoan Parasites Costia, Childonella and Trichodine


Shake Well Before Using


Squeeze Bottle Gently



Before administering any water treatment, it is wise to check your water quality levels to ensure they are within their acceptable ranges.  Remove carbon from filter before use.  Add 1 drop per gallon daily for all fish except those of the Tetra group.  FOR TETRAS: Add 1 drop per 2 gallons daily.  FOR MARINE FISH:  Add 1 drop per gallon daily in a bare aquarium.  Replace carbon 24 hours after last treatment.

Quick Cure Dosage and Administration

MAXIUM DOSAGE: 3 DAILY TREATMENTS


If further medication is required, perform a 25% water change before administering another treatment cycle.  Water will turn blue during treatment.  This is a temporary condition and will disappear in a few days.  Change 50% of water if fish show any signs of distress during treatment or an accidental overdose of this product occurs.

ACTIVE INGREDIENTS

Formalin, Malachite Green

Warnings

Do not use on:  Baby Whales, Elephant Nose, Shrimps, Snails, Living Rock, or Invertebrates.  For aquarium use only.  Keep out of reach of children.  Do not exceed recommended dosage.  May stain silicone sealant and aquarium decorations.  If swallowed, seek medical attention immediately and take product label with you.  This product contains a chemical known to the State of California to cause cancer.

How is Quick Cure Supplied

0.75 fl oz (22 mL) - Treats 400 Gallons


4 fl oz (118 mL) - Treats 2,000 Gallons


16 fl oz (1 pint) - Treats 8,000 Gallons

PACKAGE LABEL PRINCIPAL DISPLAY PANEL

Quick Cure


Distributed by:


Sergeant's Pet Care Products, Inc., Omaha NE 68130


www.sergeants.com


Made in USA

Quick Cure  formalin, malachite green  liquid

Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 21091-203 Route of Administration EXTRACORPOREAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FORMALDEHYDE (FORMALDEHYDE) FORMALDEHYDE 0.366 g  in 1 mL MALACHITE GREEN (MALACHITE GREEN) MALACHITE GREEN 0.005 g  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color blue (Dark blue-green) Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 21091-203-75 1 BOTTLE In 1 CELLO PACK contains a BOTTLE, PLASTIC 1 22 mL In 1 BOTTLE, PLASTIC This package is contained within the CELLO PACK (21091-203-75) 2 21091-203-04 118 mL In 1 BOTTLE, PLASTIC None 3 21091-203-16 473 mL In 1 BOTTLE, DISPENSING None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		04/09/2009

Labeler - Sergeant's Pet Care Products, Inc. (876995171)

Revised: 03/2010Sergeant's Pet Care Products, Inc.