Tandem DHA

Generic Name: ferrous fumarate, iron, ascorbic acid, pyridoxine hydrochloride, omega-3-acid ethyl esters and folic acid

Dosage Form: capsule
see all prescribing information for Tandem DHA DESCRIPTION: Each opaque pink capsule contains;

Ferrous Fumarate (Elemental Iron) . . . . . . . . . . . . . . . 15 mg

Vitamin C (Sodium Ascorbate)    . . . . . . . . . . . . . . . . . 20 mg FolicAcid␣␣ ................................. 1mg

Vitamin B6 (Pyridoxine HCI)␣␣    . . . . . . . . . . . . . . . . . . .    25 mg Omega-3FattyAcids␣␣ ...................... 310.1mg

PPolysaccharide Iron Complex (Elemental Iron)    ␣␣    . . . . . . (Equivalent to about 30 mg of elemental iron)

((Derived from 450 mg Fish Oil)␣␣

Docosahexaenoic Acid (DHA)␣␣    . . . . . . . . . . . . ␣␣ Eicosapentaenoic Acid (EPA)␣␣    . . . . . . . . . . . . . .

2215.12 mg 53.46 mg

Clinical Studies: The licensee U.S. Pharmaceutical Corporation and JLM Pharmatech, Inc. had jointly sponsored new research pertaining to this formulation (Liesa M. Diehl August 2005: A 14-Day Comparative Pharmacokinetic Study of Ferrous Fumarate and Ferrous Fumarate-Polysaccharide Iron Complex Administered by the Oral (Gavage) Route to Rats, Charles River Laboratories, Preclinical Services: Spencerville, OH). (Personal Communication, Study number NEM00001, August 2005). Because Ferrous Fumarate is an organic complex, it contains no free ions, either ferric or ferrous. Polysaccharide Iron Complex is clinically non-toxic. Prior studies in rats demonstrated that Polysaccharide Iron Complex (PIC), administered as a single oral dose to Sprague Dawley rats did not produce evidence of toxicity at a dosage level of 5000 mg Iron/kg: (An Acute Oral Toxicity Study in Rats with Polysaccharide-Iron Complex. T.N.Merriman, M. Aikman and R.E. Rush, Springborn Laboratories, Inc. Spencerville, Ohio Study No. 3340.1 March - April 1994). Other clinical studies had demonstrated that Polysaccharide Iron gives a good hematopoietic response with an almost complete absence of the side effects usually associated with oral iron therapy. Picinni and Ricciotti suggested in 1982, that "the therapeutic effectiveness of Polysaccharide Iron Complex when compared with iron fumarate in the treatment of iron deficiency anemia, appears to be as active as the iron fumarate and as well tolerated, however, it exerted a greater influence on the level of hemoglobin and on the number of red cells..." and that, "it has been exceptionally well tolerated by all patients" (Picinni, L.- Ricciotti, M. 1982. Therapeutic effectiveness of an iron-polysaccharide complex in comparison with iron fumarate in the treatment of iron deficiency anemias): PANMINERVA MEDICA-EUROPA MEDICA, Vol. 24, No. 3, pp. 213-220 (July - September 1982).

As mentioned above, the patented source of iron used in Tandem® DHA (Ferrous Fumarate and Polysaccharide Iron Complex) provides a high level of elemental iron with a low incidence of gastric distress. The Liesa Diehl study maintains that, "the oral combination of Ferrous Fumarate and Polysaccharide Iron Complex was better tolerated than the oral administration of Ferrous Fumarate alone." Overall, greater statistically and toxicologically significant effects in hematology and clinical chemistry parameters were observed in Group 2 animals (Ferrous Fumarate only) than were observed in Group 3 animals (Ferrous Fumarate and PIC) as compared to controls.

␣␣ CONCLUSION: Based on the results of this study, the oral combination of Ferrous Fumarate and Polysaccharide Iron Complex was better tolerated and safer than the oral administration of Ferrous Fumarate alone. The conclusion of this research stated, "that both compositions provide equivalent efficacy at increasing serum iron levels, but that the Group 3 material (i.e., the composition named in the patent), is significantly better tolerated than is Ferrous Fumarate alone, although the concentration of Ferrous Fumarate is the same in both compositions." In other words, the results support the conclusion that the addition of PIC to Ferrous Fumarate surprisingly allows the same concentration of Ferrous Fumarate to be better tolerated than the Ferrous Fumarate alone.

INDICATIONS: Tandem® DHA is a prescription prenatal vitamin-mineral preparation containing omega-3 fatty acid supplements designed to supply nutritional supplementation for women throughout pregnancy and during the postnatal period to lactating and non-lactating mothers. Tandem® DHA may also be used to improve the nutritional status of women before conception. ␣␣

␣␣CONTRAINDICATIONS: Tandem® DHA is contraindicated in patients with known hypersensitivity to any of its ingredients, including fish or fish oil; also, all iron compounds are contraindicated in patients with hemosiderosis, hemochromatosis, or hemolytic anemias. Pernicious anemia is a contraindication, as folic acid may obscure its signs and symptoms.

WARNING: Accidental overdose of iron-containing products is the leading cause of fatal poisoning in children under six. Keep this and all drugs out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

WARNING: Ingestion of more than 3 grams of omega-3 fatty acids from fish oils per day may have potential antithrombotic effects, including an increased bleeding time and INR (international normalized ratio). DHA should be avoided in patients with inherited or acquired bleeding diatheses, including those taking anticoagulants. ␣␣ WARNING: Folic acid alone is improper therapy in the treatment for pernicious anemia and other megaloblastic anemias where Vitamin B12 is deficient. ␣␣ PRECAUTIONS: General: Folic acid in doses above 0.1 mg -0.4 mg daily may obscure pernicious anemia, in that hematological remission can occur while neurological manifestations remain progressive.

Pediatric Use: Safety and effectiveness of this product have not been established in pediatric patients.

Geriatric Use: No clinical studies have been performed in patients age 65 and over to determine whether older persons respond differently from younger persons. Dosage should always begin at the low end of the dosage scale and should consider that elderly persons may have decreased hepatic, renal, or cardiac function and or concomitant diseases.

Adverse Reactions: Folic Acid: Allergic sensitizations have been reported following both oral and parenteral administration of folic acid. Ferrous Fumarate: Gastrointestinal disturbances (anorexia, nausea, diarrhea, constipation) occur occasionally, but are usually mild and may subside with continuation of therapy. Although the absorption of iron is best when taken between meals, giving Tandem® DHA after meals may control occasional G.I. disturbances. Tandem® DHA is best absorbed when taken at bedtime.

OVERDOSE: Iron: Signs and Symptoms: Iron is toxic. Acute overdosage of iron may cause nausea and vomiting and, in severe cases, cardiovascular collapse and death. Other symptoms include pallor and cyanosis, melena, shock, drowsiness and coma. The estimated overdose of orally ingested iron is 300-mg/kg body weight. When overdoses are ingested by children, severe reactions, including fatalities, have resulted. Tandem® DHA should be stored beyond the reach of children to prevent against accidental iron poisoning. Keep this and all other drugs out of the reach of children. Treatment: For specific therapy, exchange transfusion and chelating agents should be used. For general management, perform gastric lavage with sodium bicarbonate solution or milk. Administer intravenous fluids and electrolytes and use oxygen.

DOSAGE AND ADMINISTRATION: Adults (persons over 12 years of age), one (1) capsule daily, orally, between meals, or as prescribed by a physician. Do not exceed recommended dosage. Do not administer to children under the age of 12. ␣␣

Enter section text here

Tandem DHA   vitamin- mineral omega-3 supplement  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 52747-904 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FERROUS FUMARATE (IRON) IRON 15 mg IRON (IRON) IRON 15 mg ASCORBIC ACID (ASCORBIC ACID) ASCORBIC ACID 20 mg PYRIDOXINE HYDROCHLORIDE (PYRIDOXINE) PYRIDOXINE 25 mg OMEGA-3-ACID ETHYL ESTERS (OMEGA-3-ACID ETHYL ESTERS) OMEGA-3-ACID ETHYL ESTERS 310.1 mg FOLIC ACID (FOLIC ACID) FOLIC ACID 1 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color pink (opaque pink) Score score with uneven pieces Shape CAPSULE Size 22mm Flavor Imprint Code Tandem;DHA;US Contains

Packaging # NDC Package Description Multilevel Packaging 1 52747-904-60 90 CAPSULE In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		01/17/2007

Labeler - US Pharmaceutical Corporation (048318224)

Registrant - US Pharmaceutical Corporation (048318224)

Revised: 12/2009US Pharmaceutical Corporation

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Gliadel

polifeprosan 20 with carmustine implant

Dosage Form: wafer
Gliadel® WAFER     Rx only

(polifeprosan 20 with carmustine implant)

DESCRIPTION

Gliadel® Wafer (polifeprosan 20 with carmustine implant) is a sterile, off-white to pale yellow wafer approximately 1.45 cm in diameter and 1 mm thick. Each wafer contains 192.3 mg of a biodegradable polyanhydride copolymer and 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Carmustine is a nitrosourea oncolytic agent. The copolymer, polifeprosan 20, consists of poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio and is used to control the local delivery of carmustine. Carmustine is homogeneously distributed in the copolymer matrix.

The structural formula for polifeprosan 20 is:

The structural formula for carmustine is:

CLINICAL PHARMACOLOGY

Gliadel® Wafer is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine released from Gliadel® Wafer diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.

Carmustine has been shown to degrade both spontaneously and metabolically. The production of an alkylating moiety, hypothesized to be chloroethyl carbonium ion, leads to the formation of DNA cross-links.

The tumoricidal activity of Gliadel® Wafer is dependent on release of carmustine to the tumor cavity in concentrations sufficient for effective cytotoxicity.

More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolized by the liver and expired as CO2 in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by Gliadel® Wafer in human brain tissue have not been determined. Plasma levels of carmustine after Gliadel® Wafer implant were not determined. In rabbits implanted with wafers containing 3.85% carmustine, no detectible levels of carmustine were found in the plasma or cerebrospinal fluid.

Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance, and steady-state volume of distribution were 22 minutes, 56 mL/min/kg, and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200 mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2.

Gliadel® Wafers are biodegradable in human brain when implanted into the cavity after tumor resection. The rate of biodegradation is variable from patient to patient. During the biodegradation process, a wafer remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred. Data obtained from review of CT scans obtained 49 days after implantation of Gliadel® Wafer demonstrated that images consistent with wafers were visible to varying degrees in the scans of 11 of 18 patients. Data obtained at re-operation and autopsies have demonstrated wafer remnants up to 232 days after Gliadel® Wafer implantation.

Wafer remnants removed at re-operation from two patients with recurrent malignant glioma, one at 64 days and the second at 92 days after implantation, were analyzed for content. The following table presents the results of analyses completed on these remnants.

COMPOSITION OF WAFER REMNANTS REMOVED FROM TWO PATIENTS ON RE-OPERATION

Component	Patient A	Patient B
Days After Gliadel® Wafer Implantation	64	92
Anhydride Bonds	None detected	None detected
Water Content (% of wafer remnant weight)	95-97%	74-86%
Carmustine Content (% of initial)	<0.0004%	0.034%
Carboxyphenoxypropane Content (% of initial)	9%	14%
Sebacic Acid Content (% of initial)	4%	3%

The wafer remnants consisted mostly of water and monomeric components with minimal detectable carmustine present.

CLINICAL STUDIES

Primary Surgery

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with newly-diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection. This trial determined the safety and efficacy of Gliadel® Wafer implants plus surgery and radiation therapy compared to placebo implants plus surgery and radiation therapy. Two hundred and forty patients with newly-diagnosed malignant glioma were enrolled. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). Gliadel® Wafers were implanted at the time of the surgery in 120 patients and placebo wafers were implanted in 120 patients. The majority of patients received 6-8 wafers. The majority of patients (93/120, 77.5% in the Gliadel® Wafer group and 98/120, 81.7% in the placebo group) with newly-diagnosed malignant glioma received a standard course of radiotherapy (55 to 60 Gy) typically starting 3 weeks after surgery. There were 17 patients (14.2%) in the Gliadel® Wafer group and 12 patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All six patients with anaplastic oligodendroglioma received chemotherapy within 30 days of Gliadel® Wafer implantation. Patients were followed for at least three years or until death. Only one patient was lost to follow-up. Median survival increased from 11.6 months with placebo to 13.8 months with Gliadel® Wafer (p-value <0.05, log-rank test). The hazard ratio for Gliadel® Wafer treatment was 0.73 (95% CI: 0.56-0.95).

Kaplan-Meier Overall Survival Curves for Patients Undergoing Initial Surgery for a High-Grade Malignant Glioma

When only patients with Glioblastoma multiforme were included in the analysis, the hazard ratio with Gliadel® Wafer treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test).

Surgery for Recurrent Disease

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with recurrent malignant glioma. This trial determined the safety and efficacy of Gliadel® Wafer implants plus surgery compared to placebo implants plus surgery.

Ninety-five percent of the patients treated with Gliadel® Wafer had 7-8 wafers implanted. Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after repeat surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with Gliadel® Wafer. Median survival increased by 33%, from 24 weeks (5.5 months) with placebo to 32 weeks (7.4 months) with Gliadel® Wafer treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with Gliadel® Wafer treatment. Median survival of GBM patients increased by 41% from 20 weeks (4.6 months) with placebo to 28 weeks (6.4 months) with Gliadel® Wafer treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, Gliadel® Wafer produced no survival prolongation.

6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

KAPLAN-MEIER OVERALL SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

INDICATIONS AND USAGE

Gliadel® Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. Gliadel® Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.

CONTRAINDICATIONS

Gliadel® Wafer contains carmustine. Gliadel® Wafer should not be given to individuals who have demonstrated a previous hypersensitivity to carmustine or any of the components of Gliadel® Wafer.

WARNINGS

Patients undergoing craniotomy for malignant glioma and implantation of Gliadel® Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with Gliadel® Wafer, including one case leading to brain herniation.

Pregnancy: There are no studies assessing the reproductive toxicity of Gliadel® Wafer. Carmustine, the active component of Gliadel® Wafer, can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m2 basis). Carmustine was embryotoxic in rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

There are no studies of Gliadel® Wafer in pregnant women. If Gliadel® Wafer is used during pregnancy, or if the patient becomes pregnant after Gliadel® Wafer implantation, the patient must be warned of the potential hazard to the fetus.

PRECAUTIONS

General

Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus. If a communication larger than the diameter of a wafer exists, it should be closed prior to wafer implantation.

Computed tomography and magnetic resonance imaging of the head may demonstrate enhancement in the brain tissue surrounding the resection cavity after implantation of Gliadel® Wafers. This enhancement may represent edema and inflammation caused by Gliadel® Wafer or tumor progression.

Therapeutic Interactions

Interactions of Gliadel® Wafer with other drugs have not been formally evaluated.

The short-term and long-term toxicity profiles of Gliadel® Wafer when given in conjunction with chemotherapy have not been fully explored. Gliadel® Wafer, when given in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with Gliadel® Wafer. Carcinogenicity, mutagenicity and impairment of fertility studies have been conducted with carmustine, the active component of Gliadel® Wafer. Carmustine was given three times a week for six months, followed by 12 months observation, to Swiss mice at i.p. doses of 2.5 and 5.0 mg/kg (about 1/5 and 1/3 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m2 basis) and to SD rats at i.p. dose of 1.5 mg/kg (about 1/4 the recommended human dose on a mg/m2 basis). There were increases in tumor incidence in all treated animals, predominantly subcutaneous and lung neoplasms. Mutagenesis: Carmustine was mutagenic in vitro (Ames assay, human lymphoblast HGPRT assay) and clastogenic both in vitro (V79 hamster cell micronucleus assay) and in vivo (SCE assay in rodent brain tumors, mouse bone marrow micronucleus assay). Impairment of Fertility: Carmustine caused testicular degeneration at i.p. doses of 8 mg/kg/week for eight weeks (about 1.3 times the recommended human dose on a mg/m2 basis) in male rats.

Pregnancy

Pregnancy Category D: see WARNINGS.

Nursing Mothers

It is not known if either carmustine, carboxyphenoxypropane, or sebacic acid is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from carmustine in nursing infants, it is recommended that patients receiving Gliadel® Wafer discontinue nursing.

Pediatric Use

The safety and effectiveness of Gliadel® Wafer in pediatric patients have not been established.

ADVERSE REACTIONS

Adverse reactions for the trials are described in the tables below.

Primary Surgery

The following data are the most frequently occurring adverse events observed in 5% or more of the newly-diagnosed malignant glioma patients during the trial.

COMMON ADVERSE EVENTS OBSERVED IN ≥ 5% OF PATIENTS RECEIVING Gliadel® WAFER AT INITIAL SURGERY

Body System    Adverse Event	Gliadel® Wafer [N=120] n (%)	Placebo [N=120] n (%)
*Adverse events coded to the COSTART term "aggravation reaction" were usually events involving tumor/disease progression or general deterioration of condition (e.g. condition/health/Karnofsky/neurological/physical deterioration).
Body as a Whole
Aggravation reaction*	98 (82)	95 (79)
Headache	33 (28)	44 (37)
Asthenia	26 (22)	18 (15)
Infection	22 (18)	24 (20)
Fever	21 (18)	21 (18)
Pain	16 (13)	18 (15)
Abdominal pain	10 (8)	2 (2)
Back pain	8 (7)	4 (3)
Face edema	7 (6)	6 (5)
Abscess	6 (5)	3 (3)
Accidental injury	6 (5)	8 (7)
Chest pain	6 (5)	0
Allergic reaction	2 (2)	6 (5)
Cardiovascular system
Deep thrombophlebitis	12 (10)	11 (9)
Pulmonary embolus	10 (8)	10 (8)
Hemorrhage	8 (7)	7 (6)
Digestive system
Nausea	26 (22)	20 (17)
Vomiting	25 (21)	19 (16)
Constipation	23 (19)	14 (12)
Diarrhea	6 (5)	5 (4)
Liver function tests abnormal	1 (1)	6 (5)
Endocrine system
Diabetes mellitus	6 (5)	5 (4)
Cushings syndrome	4 (3)	6 (5)
Metabolic and nutritional disorders
Healing abnormal	19 (16)	14 (12)
Peripheral edema	11 (9)	11 (9)
Musculoskeletal system
Myasthenia	5 (4)	6 (5)
Nervous system
Hemiplegia	49 (41)	53 (44)
Convulsion	40 (33)	45 (38)
Confusion	28 (23)	25 (21)
Brain edema	27 (23)	23 (19)
Aphasia	21 (18)	22 (18)
Depression	19 (16)	12 (10)
Somnolence	13 (11)	18 (15)
Speech disorder	13 (11)	10 (8)
Amnesia	11 (9)	12 (10)
Intracranial hypertension	11 (9)	2 (2)
Personality disorder	10 (8)	9 (8)
Anxiety	8 (7)	5 (4)
Facial paralysis	8 (7)	5 (4)
Neuropathy	8 (7)	12 (10)
Ataxia	7 (6)	5 (4)
Hypesthesia	7 (6)	6 (5)
Paresthesia	7 (6)	10 (8)
Thinking abnormal	7 (6)	10 (8)
Abnormal gait	6 (5)	6 (5)
Dizziness	6 (5)	11 (9)
Grand mal convulsion	6 (5)	5 (4)
Hallucinations	6 (5)	4 (3)
Insomnia	6 (5)	7 (6)
Tremor	6 (5)	8 (7)
Coma	5 (4)	6 (5)
Incoordination	3 (3)	8 (7)
Hypokinesia	2 (2)	8 (7)
Respiratory system
Pneumonia	10 (8)	9 (8)
Dyspnea	4 (3)	8 (7)
Skin and appendages
Rash	14 (12)	13 (11)
Alopecia	12 (10)	14 (12)
Special senses
Conjunctival edema	8 (7)	8 (7)
Abnormal vision	7 (6)	7 (6)
Visual field defect	6 (5)	8 (7)
Eye disorder	3 (3)	6 (5)
Diplopia	1 (1)	6 (5)
Urogenital system
Urinary tract infection	10 (8)	13 (11)
Urinary incontinence	9 (8)	9 (8)

Surgery for Recurrent Disease

The following post-operative adverse events were observed in 4% or more of the patients receiving Gliadel® Wafer at recurrent surgery. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the Gliadel® Wafer group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.

COMMON ADVERSE EVENTS OBSERVED IN ≥ 4% OF PATIENTS RECEIVING Gliadel® WAFER AT SURGERY FOR RECURRENT DISEASE

Body System Adverse Event	Gliadel® Wafer with Carmustine [N=110] n (%)	PLACEBO Wafer without Carmustine [N=112] n (%)
*p < 0.05 for comparison of Gliadel® Wafer versus placebo groups
Body as a Whole
Fever	13 (12)	9 (8)
Pain*	8 (7)	1 (1)
Digestive System
Nausea and Vomiting	9 (8)	7 (6)
Metabolic and Nutritional Disorders
Healing Abnormal*	15 (14)	6 (5)
Nervous System
Convulsion	21 (19)	21 (19)
Hemiplegia	21 (19)	22 (20)
Headache	16 (15)	14 (13)
Somnolence	15 (14)	12 (11)
Confusion	11 (10)	9 (8)
Aphasia	10 (9)	12 (11)
Stupor	7 (6)	7 (6)
Brain Edema	4 (4)	1 (1)
Intracranial Hypertension	4 (4)	7 (6)
Meningitis or Abscess	4 (4)	1 (1)
Skin and Appendages
Rash	6 (5)	4 (4)
Urogenital System
Urinary Tract Infection	23 (21)	19 (17)

Post-marketing experience includes spontaneous reports of cyst formation after Gliadel® wafer implantation. These occurred at varying time intervals post-implantation. Cyst formation has also been reported in patients following resection of malignant glioma who have not had Gliadel® implanted.

The following four categories of adverse events are possibly related to treatment with Gliadel® Wafer. The frequency with which they occurred in the randomized trials along with descriptive detail is provided below.

1. Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving Gliadel® Wafer and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of Gliadel® Wafer-treated patients and 4.2% of placebo treated patients. The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the Gliadel® Wafer group and 4.2% in the placebo group. The time from surgery to the onset of the first post-operative seizure did not differ between the Gliadel® Wafer and placebo treated patients.

In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving Gliadel® Wafer and placebo. In this study, 12/22 (54%) of patients treated with Gliadel® Wafer and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with Gliadel® Wafer and 61 days in placebo patients.

2. Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with Gliadel® Wafer and in 19.2% of patients treated with placebo. Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of Gliadel® Wafer or its remnants.

3. Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of Gliadel® Wafer: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of Gliadel® Wafer treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of Gliadel® Wafer recipients and 0.8% of those given placebo. During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak.

In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in Gliadel® Wafer treated patients and 5% in patients receiving placebo wafers.

4. Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with Gliadel® Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with Gliadel® Wafer and 1% in patients receiving placebo.

The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with Gliadel® Wafer in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether Gliadel® Wafer caused these events cannot be determined.

Body as a Whole: peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%)

Cardiovascular System: hypertension (3%); hypotension (1%)

Digestive System: diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)

Hemic and Lymphatic System: thrombocytopenia (1%); leukocytosis (1%)

Metabolic and Nutritional Disorders: hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)

Musculoskeletal System: infection (1%)

Nervous System: hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with Gliadel® Wafer.

Respiratory System: infection (2%); aspiration pneumonia (1%)

Skin and Appendages: rash (2%)

Special Senses: visual field defect (2%); eye pain (1%)

Urogenital System: urinary incontinence (2%)

OVERDOSAGE

There is no clinical experience with use of more than eight Gliadel® Wafers per surgical procedure.

DOSAGE AND ADMINISTRATION

Each Gliadel® Wafer contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight wafers are implanted. It is recommended that eight wafers be placed in the resection cavity if the size and shape of it allows. Should the size and shape not accommodate eight wafers, the maximum number of wafers as allowed should be placed. Since there is no clinical experience, no more than eight wafers should be used per surgical procedure.

Handling and Disposal1-7: Wafers should only be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use of double gloves is recommended and the outer gloves should be discarded into a biohazard waste container after use. A surgical instrument dedicated to the handling of the wafers should be used for wafer implantation. If repeat neurosurgical intervention is indicated, any wafer or wafer remnant should be handled as a potentially cytotoxic agent.

Gliadel® Wafer should be handled with care. The aluminum foil laminate pouches containing Gliadel® Wafer should be delivered to the operating room and remain unopened until ready to implant the wafers. The outside surface of the outer foil pouch is not sterile.

Instructions for Opening Pouch Containing Gliadel® Wafer

Figure 1: To remove the sterile inner pouch from the outer pouch, locate the folded corner and slowly pull in an outward motion.

Figure 2: Do NOT pull in a downward motion rolling knuckles over the pouch. This may exert pressure on the wafer and cause it to break.

Figure 3: Remove the inner pouch by grabbing hold of the crimped edge and pulling upward.

Figure 4: To open the inner pouch, gently hold the crimped edge and cut in an arc-like fashion around the wafer.

Figure 5: To remove the Gliadel® Wafer, gently grasp the wafer with the aid of forceps and place it onto a designated sterile field.

Once the tumor is resected, tumor pathology is confirmed, and hemostasis is obtained, up to eight Gliadel® Wafers (polifeprosan 20 with carmustine implant) may be placed to cover as much of the resection cavity as possible. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but wafers broken in more than two pieces should be discarded in a biohazard container. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, the resection cavity should be irrigated and the dura closed in a water tight fashion.

Unopened foil pouches may be kept at ambient room temperature for a maximum of six hours at a time.

HOW SUPPLIED

Gliadel® Wafer is available in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile.

Gliadel® Wafer must be stored at or below -20°C (-4°F).

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.


2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):1590-1592.


3. National Study Commission on Cytotoxic Exposure -- Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.


4. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.


5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA -- A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263.


6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp Pharm, 1990; 47:1033-1049.


7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm, 1986; 43:1193-1204.

NDC: 62856-177-08

CAUTION: FEDERAL LAW PROHIBITS DISPENSING WITHOUT PRESCRIPTION.

Manufactured by

Eisai Inc.

Woodcliff Lake, NJ 07677

Rev. 04/2010

201241

PRINCIPAL DISPLAY PANEL

NDC 62856-177-08

Caution Card:

Pouch Label:

Box Label:

  

Gliadel  polifeprosan 20 with carmustine implant  wafer

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 62856-177 Route of Administration INTRACAVITARY DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CARMUSTINE (CARMUSTINE) CARMUSTINE 7.7 mg

Inactive Ingredients Ingredient Name Strength POLIFEPROSAN 20

Product Characteristics Color white (white) Score no score Shape ROUND (ROUND) Size 15mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 62856-177-08 8 POUCH In 1 BOX contains a POUCH 1 1 WAFER In 1 POUCH This package is contained within the BOX (62856-177-08)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020637	09/24/1996

Labeler - Eisai Inc. (831600833)

Registrant - Eisai Inc. (831600833)

Establishment
Name	Address	ID/FEI	Operations
Eisai Inc.		624009093	MANUFACTURE

Revised: 05/2010Eisai Inc.

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Tranylcypromine

Pronunciation: tran-ill-SIP-row-meen
Generic Name: Tranylcypromine
Brand Name: Parnate

Antidepressants may increase the risk of suicidal thoughts or actions in children, teenagers, and young adults. However, depression and certain other mental problems may also increase the risk of suicide. Talk with the patient's doctor to be sure that the benefits of using Tranylcypromine outweigh the risks.

Family and caregivers must closely watch patients who take Tranylcypromine. It is important to keep in close contact with the patient's doctor. Tell the doctor right away if the patient has symptoms like worsened depression, suicidal thoughts, or changes in behavior. Discuss any questions with the patient's doctor.

Tranylcypromine is used for:

Treating depression. It may also be used for other conditions as determined by your doctor.

Tranylcypromine is a monoamine oxidase inhibitor (MAOI). It works by blocking the action of the enzyme (monoamine oxidase) that breaks down the body's mood-elevating chemicals (dopamine, norepinephrine, and serotonin). This produces an increase in the activity of these mood-elevating chemicals.

Do NOT use Tranylcypromine if:

• you are allergic to any ingredient in Tranylcypromine


• you have a history of stroke, heart disease, congestive heart failure, a brain disease, headaches, liver disease or abnormal liver function tests, high blood pressure, or an adrenal gland tumor (pheochromocytoma)


• you will be having surgery


• you eat foods with a high tyramine content (eg, aged cheeses, sour cream, red wines, beer, bologna, pepperoni, salami, summer sausage, pickled herring, liver, meat prepared with tenderizers, canned figs, raisins, bananas, avocados, soy sauce, fava beans, yeast extracts). Ask your health care provider for a complete list of foods you should avoid.


• you drink alcohol or consume large quantities of foods or drinks that contain caffeine (eg, coffee, tea, chocolate, cola)


• you are taking an amphetamine, an anorexiant (eg, sibutramine, phentermine), an antihistamine (eg, loratadine), apraclonidine, bupropion, buspirone, a catechol-O-methyltransferase (COMT) inhibitor (eg, entacapone), dexmethylphenidate, dextromethorphan, a diuretic (eg, hydrochlorothiazide), certain herbal products (eg, ma huang), levodopa, meperidine, a narcotic pain medicine (eg, codeine), nefazodone, a norepinephrine reuptake inhibitor (eg, atomoxetine), a selective serotonin reuptake inhibitor (SSRI) (eg, fluoxetine, citalopram), a serotonin-norepinephrine reuptake inhibitor (SNRI) (eg, duloxetine, venlafaxine), a sedative, a sympathomimetic (eg, pseudoephedrine, albuterol), tetrabenazine, a tetracyclic antidepressant (eg, mirtazapine), tramadol, trazodone, a triptan (eg, sumatriptan, zolmitriptan), or tryptophan


• you are taking or have taken carbamazepine, cyclobenzaprine, furazolidone, linezolid, maprotiline, methylene blue, another MAOI (eg, phenelzine), or a tricyclic antidepressant (eg, amitriptyline, doxepin) within the last 7 days


• you are taking certain medicine for high blood pressure (eg, guanethidine, methyldopa, reserpine)

Contact your doctor or health care provider right away if any of these apply to you.

Video: Treatment for Depression

Treatments for depression are getting better everyday and there are things you can start doing right away.

Before using Tranylcypromine:

Some medical conditions may interact with Tranylcypromine. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have asthma, bipolar mood disorder, bronchitis, an irregular heartbeat, diabetes, seizures (eg, epilepsy), an overactive thyroid, Parkinson disease, the blood disease porphyria, kidney problems, or heart problems


• if you will be having a certain type of imaging exam (myelography)


• if you have a history of substance or alcohol abuse or dependence


• if you or a member of your family have ever had bipolar disorder, depression, other mental or mood problems (eg, anxiety), or suicidal thoughts or actions


• if you are taking disulfiram


• if you are taking medicine for high blood pressure

Some MEDICINES MAY INTERACT with Tranylcypromine. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Amphetamines, anorexiants (eg, sibutramine , phentermine), antihistamines (eg, loratadine), apraclonidine, bupropion, buspirone, carbamazepine, COMT inhibitors (eg, entacapone), cyclobenzaprine, dexmethylphenidate, dextromethorphan, diuretics (eg, hydrochlorothiazide), certain herbal products (eg, ma huang), furazolidone, levodopa, linezolid, methylene blue, meperidine, narcotic pain medicines (eg, codeine), nefazodone, norepinephrine reuptake inhibitors (eg, atomoxetine), SSRIs (eg, fluoxetine, citalopram), SNRIs (eg, duloxetine, venlafaxine), sedatives, sympathomimetics (eg, pseudoephedrine, albuterol), tetrabenazine, tetracyclic antidepressants (eg, maprotiline, mirtazapine), tramadol, trazodone, tricyclic antidepressants (eg, amitriptyline, doxepin), triptans (eg, sumatriptan, zolmitriptan), tryptophan, certain medicines for blood pressure (eg, guanethidine, methyldopa, reserpine), or another MAOI (eg, phenelzine) because severe side effects may occur


• Many prescription and nonprescription medicines (eg, used for ADHD, diabetes, depression, Parkinson disease, glaucoma, headaches, heart or blood vessel problems, pain, anesthesia, cold and flu, allergies, high blood pressure, mental or mood problems, weight loss, seizures), multivitamin products, and herbal or dietary supplements (eg, herbal teas, coenzyme Q10, garlic, ginseng, ginkgo, St. John's wort) may interact with Tranylcypromine, increasing the risk of side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tranylcypromine may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Tranylcypromine:

Use Tranylcypromine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tranylcypromine comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Tranylcypromine refilled.


• Take Tranylcypromine by mouth with or without food.


• Continue to take Tranylcypromine even if you feel well. Do not miss any doses.


• If you miss a dose of Tranylcypromine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tranylcypromine.

Important safety information:

• Tranylcypromine may cause drowsiness, dizziness, or fainting. These effects may be worse if you take it with alcohol or certain medicines. Use Tranylcypromine with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Eating foods high in tyramine (eg, aged cheeses, red wines, beer, certain meats and sausages, liver, sour cream, soy sauce, raisins, bananas, avocados) while you use an MAOI may cause severe high blood pressure. This could occur for up to 2 weeks after you stop taking an MAOI. Do not eat foods high in tyramine while you take Tranylcypromine. Ask your health care provider for a complete list of foods you should avoid. Seek medical attention at once if symptoms of severe high blood pressure occur. These may include severe headache, fast or irregular heartbeat, sore or stiff neck, nausea, vomiting, sweating, enlarged pupils, or sensitivity to light.


• Avoid large amounts of food or drink that have caffeine (eg, coffee, tea, cocoa, cola, chocolate).


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Tranylcypromine; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Tranylcypromine may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Children and teenagers who take Tranylcypromine may be at increased risk for suicidal thoughts or actions. Adults may also be affected. The risk may be greater in patients who have had suicidal thoughts or actions in the past. The risk may also be greater in patients who have had bipolar (manic-depressive) illness, or if their family members have had it. Watch patients who take Tranylcypromine closely. Contact the doctor at once if new, worsened, or sudden symptoms such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur.


• Tranylcypromine may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Tranylcypromine. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Tell your doctor or dentist that you take Tranylcypromine before you receive any medical or dental care, emergency care, or surgery.


• Before you begin taking any new medicine, either prescription or nonprescription, check with your doctor or pharmacist.


• Diabetes patients - Tranylcypromine may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including blood pressure monitoring, may be performed while you use Tranylcypromine. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Tranylcypromine with caution in the ELDERLY; they may be more sensitive to its effects, especially difficulty sleeping and enlarged prostate.


• Tranylcypromine should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed. CHILDREN taking Tranylcypromine may be at increased risk of suicidal thoughts and behaviors.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tranylcypromine while you are pregnant. Tranylcypromine is found in breast milk. Do not breast-feed while taking Tranylcypromine.

If you stop taking Tranylcypromine suddenly, you may have WITHDRAWAL symptoms. These may include restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, and diarrhea.

Possible side effects of Tranylcypromine:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; drowsiness; dry mouth; stomach pain; tremors; upset stomach; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bizarre behavior; blurred vision; chest pain; difficulty sleeping; dilated pupils; dizziness; fainting; fast, slow, or irregular heartbeat; feelings of irritability and hostility; fever; headache; impulsive behavior or other unusual changes in behavior; nausea; new or worsening mental or mood changes (eg, agitation, anxiety, depression); panic attacks; pounding in the chest; sensitivity to light; severe nervousness; severe restlessness; sleeplessness; sore or stiff neck; suicidal thoughts or actions; sweating (sometimes with fever or cold, clammy skin); vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Tranylcypromine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include agitation; anxiety; confusion; dizziness; drowsiness; excitement; fainting; fast heartbeat; fever; flushing; headache; irritability; muscle twitching; new or worsening trouble sleeping; restlessness; seizures; sweating; weakness.

Proper storage of Tranylcypromine:

Store Tranylcypromine at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tranylcypromine out of the reach of children and away from pets.

General information:

• If you have any questions about Tranylcypromine, please talk with your doctor, pharmacist, or other health care provider.


• Tranylcypromine is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Tranylcypromine. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Calcium Folinate 7.5 mg / mL Injection

1. Name Of The Medicinal Product

Calcium Folinate 7.5 mg/mL Injection

2. Qualitative And Quantitative Composition

Each ampoule of 2 ml solution contains 7.5 mg/ml of folinic acid provided as calcium folinate.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for Injection

4. Clinical Particulars

4.1 Therapeutic Indications

Calcium folinate is indicated

a) to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as “Calcium Folinate Rescue”;

b) in combination with 5-fluorouracil in cytotoxic therapy.

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

Calcium folinate rescue in methotrexate therapy:

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and should be considered with doses of 100 mg – 500 mg/m² body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is>0.5 µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:
> 0.5 µmol/l	15 mg/m²
> 1.0 µmol/l	100 mg/m²
> 2.0 µmol/l	200 mg/m²

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.

The following regimens have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of these combinations in children:

Bimonthly regimen: Calcium folinate 200 mg/m² by intravenous infusion over two hours, followed by bolus 400 mg/m² of 5-FU and 22-hour infusion of 5-FU (600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours plus 500 mg/m² 5-fluorouracil as i.v. bolus injection in the middle or at the end of the calcium folinate infusion.

Monthly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as i.v. bolus injection during five consecutive days.

For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

The number of repeat cycles used is at the discretion of the clinician.

Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine:

Trimetrexate toxicity:

• Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

• Overdosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours for 3 days.

Trimethoprim toxicity:

• After stopping trimethoprim, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

• In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

4.3 Contraindications

• Known hypersensitivity to calcium folinate, or to any of the excipients.

• Pernicious anaemia or other anaemias due to vitamin B12 deficiency.

Regarding the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6, “Pregnancy and Lactation” and the summaries of product characteristics for methotrexate- and 5-fluorouracil- containing medicinal products.

4.4 Special Warnings And Precautions For Use

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate death has been reported.

General

Calcium folinate should be used with methotrexate or 5-fluorouracil only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.

Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interactions).

Calcium folinate/5-fluorouracil

Calcium folinate may enhance the toxicity risk of 5-fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea, which may be dose limiting. When calcium folinate and 5-fluorouracil are used in combination, the 5- fluorouracil dosage has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone.

Combined 5-fluorouracil/calcium folinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.

Because diarrhoea may be a sign of gastrointestinal toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and/or stomatitis occur, it is advisable to reduce the dose of 5-FU until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to their illness are prone to these toxicities. Therefore, particular care should be taken when treating these patients.

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-fluorouracil.

Calcium folinate must not be mixed with 5-fluorouracil in the same IV injection or infusion.

Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate treatment and calcium supplementation should be provided if calcium levels are low.

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.

Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SPC for methotrexate). The presence of preexisting- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.

Excessive calcium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.

An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

The possibility that the patient is taking other medications that interact with methotrexate (eg, medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also sections 4.4 and 4.8).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil (see sections 4.2, 4.4 and 4.8).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

Please refer also to the summaries of product characteristics for methotrexate-, other folate antagonists and 5-fluorouracil- containing medicinal products.

Lactation

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

4.8 Undesirable Effects

Immune system disorders

Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

Gastrointestinal disorders

Rare (0.01-0.1%): gastrointestinal disorders after high doses.

Neurological disorders

Rare (0.01-0.1%): increase in the frequency of attacks in epileptics (see also section 4.5 Interactions...).

General disorders and administration site conditions

Uncommon (0.1-1%): fever has been observed after administration of calcium folinate as solution for injection.

Combination therapy with 5-fluorouracil:

Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities:

Monthly regimen:

Gastrointestinal disorders

Very common (>10%): vomiting and nausea

General disorders and administration site conditions

Very common (>10%): (severe) mucosal toxicity.

No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).

Weekly regimen:

Gastrointestinal disorders

Very common (>10%): diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.

4.9 Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC code: V03AF03

Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme forms of folic acid.

Calcium folinate is also frequently used in the biochemical modulation of fluoropyridine (5-FU) to enhance its cytotoxic activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis, and calcium folinate enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5FU-TS complex and increasing activity.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

5.2 Pharmacokinetic Properties

Absorption

Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known.

Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration.

AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively.

The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

5.3 Preclinical Safety Data

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injections

6.2 Incompatibilities

Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.

Droperidol

1. Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml, immediate precipitation in direct admixture in syringe for 5 minutes at 25° C followed by 8 minutes of centrifugation.

2. Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml, immediate precipitation when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections.

Fluorouracil

Calcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32° C in polyvinyl chloride containers.

Foscarnet

Foscarnet 24 mg/ml with calcium folinate 20 mg/ml formation of a cloudy yellow solution reported.

6.3 Shelf Life

Product as packaged for sale: 24 months.

In use: From a microbial point of view, the product should 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 mot be longer than 24 hours at 2 to 8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (+2°C to +8°C).

Store ampoules in outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Clear 2ml Type I Glass Ampoules.Presented in packs of 5 ampoules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused portion of the solution should be disposed of in accordance with the local requirements.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

UK

8. Marketing Authorisation Number(S)

PL 04515/0033

9. Date Of First Authorisation/Renewal Of The Authorisation

March 2003

10. Date Of Revision Of The Text

December 2007