Octreotide 200micrograms / ml solution for injection

1. Name Of The Medicinal Product

Octreotide 200 micrograms/ml solution for injection

2. Qualitative And Quantitative Composition

One multidose vial contains octreotide acetate equivalent to 1000 micrograms of octreotide in 5 ml.

For full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Solution for injection.

5ml vials containing clear colourless solution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

GEP tumours

For the relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

• carcinoid tumours with features of carcinoid syndrome

• VIPomas

• glucagonomas

Octreotide is not antitumour therapy and is not curative in these patients.

Acromegaly

For symptomatic control and reduction of growth hormone and somatomedin c plasma levels in patients with acromegaly:

• in short term treatment, prior to pituitary surgery, or

• in long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, or in the interim period until radiotherapy becomes effective.

Octreotide is indicated for acromegalic patients for whom surgery is inappropriate.

Evidence from short term studies demonstrate that tumour size is reduced in some patients (prior to surgery); further tumour shrinkage however cannot be expected as a feature of continued long term treatment.

Prevention of complications following pancreatic surgery

Route of administration

Subcutaneous or intravenous use.

4.2 Posology And Method Of Administration

GEP tumours

Initially 0.05 mg once or twice daily by s.c. injection. Depending on response, dosage can be gradually increased to 0.2 mg three times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses are variable.

The recommended route of administration is subcutaneous, however, in instances where a rapid response is required, e.g. carcinoid crises, the initial recommended dose of octreotide may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring the cardiac rhythm.

In carcinoid tumours, if there is no beneficial effect within a week, continued therapy is not recommended.

Acromegaly

0.1 – 0.2 mg three times daily by s.c. injection. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH less than 2.5ng/ml, 5mU/l; IGF-1 within normal range) and clinical symptoms, and on tolerability. For patients on a stable dose of octreotide, assessment of GH should be made every 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less adequate.

If no relevant reduction of growth hormone levels and no improvement of clinical symptoms have been achieved within three months of starting treatment, therapy should be discontinued.

For the prevention of complications following pancreatic surgery

0.1 mg three times daily by subcutaneous injection for 7 consecutive days, starting on the day of operation at least one hour before laparotomy.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. therefore, no dose adjustment of octreotide is necessary.

Use in patients with impaired hepatic function

In a study with octreotide administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In patients with liver cirrhosis, an adjustment of the maintenance dose may therefore be necessary.

Use in the elderly

In elderly patients treated with octreotide, there is no evidence for reduced tolerability or altered dosage requirements.

Use in children

Experience with octreotide in children is very limited.

4.3 Contraindications

Known hypersensitivity to octreotide or to any component of the formulations (see 6.1 List of excipients).

4.4 Special Warnings And Precautions For Use

As growth hormone secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.

Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by octreotide may occur infrequently, with rapid recurrence of severe symptoms.

Octreotide may increase the depth and duration of hypoglycaemia in patients with insulinoma. This is because it is relatively more potent in inhibiting growth hormone and glucagon secretion than in inhibiting insulin and because its duration of insulin inhibition is shorter. If octreotide is given to a patient with insulinoma, close monitoring is necessary on introduction of therapy and at each change of dosage. Marked fluctuations of blood glucose may be reduced by more frequent administration of octreotide.

Octreotide may reduce insulin or oral hypoglycaemic requirements in patients with type I diabetes mellitus. In non-diabetics and type II diabetics with particularly intact insulin reserves, octreotide administration can result in prandial increases in glycaemia.

Thyroid function should be monitored in patients receiving long-term octreotide therapy.

Octreotide exerts an inhibiting effect on gallbladder motility, bile acid secretion and bile flow and there is an acknowledged association with the development of gallstones. The incidence of gallstone formation with octreotide treatment is estimated to be between 15 - 30 %.

Ultrasonic examination of the gallbladder, before and at about 6 to 12 month intervals during octreotide therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated in the normal manner with due attention to abrupt withdrawal of the drug.

In patients with cirrhosis, dosage adjustment may be necessary (see Section 4.2 Posology and Method of Administration).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. carbamazepine, digoxin, warfarin and terfenadine).

4.6 Pregnancy And Lactation

Experience with octreotide in pregnant or nursing women is very limited, and they should therefore be given the drug only under compelling circumstances.

Women receiving treatment with octreotide should not breastfeed their infants.

4.7 Effects On Ability To Drive And Use Machines

No data exists on the effects of octreotide on the ability to drive and use machines.

4.8 Undesirable Effects

The main side-effects are local and gastrointestinal.

Body as a whole

Rare: hypersensitivity skin reactions; hair loss and isolated reports of anaphylactic reactions have been observed.

Cardiovascular system

Isolated cases of bradycardia.

Gastrointestinal system

Anorexia, nausea, vomiting, abdominal pain, abdominal bloating, flatulence, loose stools, diarrhoea and steatorrhea. Although measured faecal fate excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption. In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. Occurrrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.

Hepatobiliary

Prolonged use of octreotide may result in gallstone formation (see 4.4 Special warnings and precautions for use), and there have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

There have been isolated reports of hepatic dysfunctions associated with octreotide administration. These consist of

• acute hepatitis, without cholestasis, where transaminase values have normalised on withdrawal of octreotide, or

• slow development of hyperbilirubinaemia in association with elevation of alkaline phosphatase, gamma-glutamyl transferase and, to a lesser extent, transaminases.

Pancreas

Because of its inhibitory action on growth hormone, glucagon, and insulin release, octreotide may affect glucose regulation. Postprandial glucose tolerance may be impaired and, in some instances, the state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been observed within the first hours or days of octreotide treatment and resolves on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide treatment.

Local reactions

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection.

4.9 Overdose

Doses of up to 2000 microgrammes octreotide given as subcutaneous tid for several months have been well tolerated.

No life-threatening reactions have been reported after acute overdosage. The maximum single dose given to an adult so far has been 1 mg by intravenous bolus injection. The observed signs and symptoms were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours of drug administration.

One patient has been reported to have received an accidental overdosage of octreotide by continuous infusion (250 microgrammes per hour for forty eight hours instead of 25 microgrammes per hour). He experienced no side-effects.

The management of overdosage is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antigrowth hormones (ATC code H01B C02).

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone and of peptides and serotonin produced within the gastroenteropancreatic endocrine (GEP) system.

In animals, octreotide is a more potent inhibitor of growth hormone, glucagon and insulin release than somatostatin with greater selectivity for growth hormone and glucagon suppression.

In normal healthy subjects octreotide, like somatostatin, has been shown to inhibit

• release of growth hormone stimulated by arginine, exercise and insulin-induced hypoglycaemia

• postprandial release of insulin, glucagon, gastrin other peptides of the gastroenteropancreatic system; arginine-stimulated release of insulin and glucagon and

• thyrotropin-releasing hormone (TRH) - stimulated release of thyroid stimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits growth hormone preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. growth hormone in patients with acromegaly).

For patients undergoing pancreatic surgery, the peri and post-operative administration of octreotide reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).

In patients with acromegaly, octreotide consistently lowers GH and normalises IGF-1 serum concentrations in the majority of patients. In most patients, octreotide markedly reduces the clinical symptoms of the disease , such as headache, perspiration, paresthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In individual patients with GH-secreting pituitary adenoma, octreotide was reported to lead to shrinkage of the tumour mass.

For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with octreotide provides continuous control of symptoms related to the underlying disease. The effects of octreotide in different types of gastroenteropancreatic tumours are as follows:

Carcinoid tumours

Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a falling plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas

Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

5.2 Pharmacokinetic Properties

Absorption

After subcutaneous injection, octreotide is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.

Distribution

The volume of distribution is 0.27 l/kg and the total body clearance 160 ml/min. Plasma protein binding amounts to 65 %. The amount of octreotide bound to blood cells is negligible.

Elimination

The elimination half-life after subcutaneous administrations is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and 90 minutes respectively. About 32 % is excreted unchanged into the urine.

5.3 Preclinical Safety Data

Preclinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Studies in animals showed transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic, or other reproduction effects.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium acetate trihydrate

Phenol

Glacial acetic acid

Sodium chloride

Water for injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

For prolonged storage, vials should be stored between 2ºC and 8ºC. For day-to-day use they may be stored at room temperature for up to two weeks. Protect from light. Do not freeze.

6.5 Nature And Contents Of Container

5 ml vial of uncoloured glass containing clear colourless solution.

Boxes of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

For i.v. use octreotide should be diluted with normal saline to a ratio of not less than 1 vol : 1 vol and not more than 1 vol : 9 vol . Dilution of octreotide with glucose solution is not recommended.

If octreotide has been diluted, the prepared solution may be kept at room temperature but should be administered within 8 hours of preparation.

To prevent contamination, it is recommended to puncture the cap of the vial not more than 10 times.

To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

7. Marketing Authorisation Holder

Sun Pharmaceuticals UK Ltd

1200 Century Way,

Thorpe Business Park,

Colton,

Leeds,

W Yorkshire,

LS15 8ZA

UK

8. Marketing Authorisation Number(S)

PL 24897/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

12 May 2008

10. Date Of Revision Of The Text

April 2010

Zoster Vaccine Live

Class: Vaccines
VA Class: IM100
Brands: Zostavax

Introduction

Live, attenuated virus vaccine.^{1 2 3 4 6 15} Zoster vaccine live contains attenuated varicella zoster virus (VZV) of the Oka/Merck strain and is used to boost active immunity to VZV.^{1 2 3 4 6 15}

Uses for Zoster Vaccine Live

Prevention of Herpes Zoster

Prevention of herpes zoster (shingles, zoster) in immunocompetent adults ≥60 years of age.^{1 2 6 14}

Herpes zoster is caused by reactivation of varicella zoster virus (VZV) infection.^{1 2 6 14} Zoster vaccine is used to boost active immunity to VZV, thereby reducing risk of VZV reactivation.^{1 2 3 4 15} The vaccine may also reduce frequency, severity, and/or duration of postherpetic neuralgia (PHN) in those who develop herpes zoster despite vaccination.^{1 2 6 14}

USPHS Advisory Committee on Immunization Practices (ACIP), American Academy of Family Physicians (AAFP), American College of Obstetricians and Gynecologists (ACOG), and American College of Physicians (ACP) recommend that all adults ≥60 years of age receive a single dose of zoster vaccine, unless contraindicated.^{6 20} (See Contraindications under Cautions.)

Although safety and efficacy not established in patients with a prior history of herpes zoster,¹ ACIP and others state the vaccine can be used in those with or without a prior episode of herpes zoster, unless a medical condition is present that is considered a contraindication or precaution for use of the vaccine.^{6 19}

Not indicated for treatment of herpes zoster or PHN.^{1 6} Not indicated for use in individuals with acute zoster infection in an attempt to prevent development of PHN.⁶

Not used for prevention of primary varicella infection (chickenpox).¹ Not a substitute for varicella vaccine (Varivax).^{1 6}

Not recommended for individuals of any age who have previously received varicella vaccine.⁶ Most individuals ≥60 years of age will not have received varicella vaccine.⁶

Not used in children, adolescents, or adults <60 years of age.^{1 6}

Zoster Vaccine Live Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection, preferably in the deltoid region of the upper arm (e.g., upper-outer triceps).^{1 6 8}

Do not administer IM or intravascularly.^{1 6}

Administer immediately following reconstitution to minimize loss of potency and ensure an adequate immunizing dose.¹

Use separate needles for reconstitution and administration.¹

Do not mix with any other vaccine or solution.⁸

Reconstitution

Lyophilized zoster vaccine must be kept frozen at -15°C or lower.^{1 6 17} (See Storage under Stability.) Reconstitute immediately following removal from the freezer.^{1 17}

To reconstitute, add entire contents of the vial containing diluent provided by the manufacturer to the vial of lyophilized vaccine.^{1 17} To avoid excessive foaming, slowly inject diluent into vial of lyophilized vaccine and agitate gently.¹ Use only the diluent supplied by the manufacturer.^{1 6 21}

Use sterile syringes and needles free of preservatives, antiseptics, and detergents to avoid inactivating the live virus vaccine.^{1 6 8}

Gently agitate reconstituted vaccine to mix thoroughly.¹ Reconstituted vaccine is a semi-hazy to translucent off-white to pale yellow suspension.¹

Dosage

Adults

Prevention of Herpes Zoster

Adults ≥60 Years of Age

Sub-Q

Single dose consisting of the entire contents (0.65 mL) of a reconstituted single-dose vial.^{1 6 20}

Duration of protection following the recommended single dose is at least 4 years.^{1 3 5 6} Need for revaccination or additional (booster) doses not determined.¹ (See Duration of Immunity under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹

Renal Impairment

No specific dosage recommendations.¹

Cautions for Zoster Vaccine Live

Contraindications

• 
  

  History of anaphylactic/anaphylactoid reactions to gelatin, neomycin, or any other vaccine component.^{1 6} (See Sensitivity Reactions under Cautions.)

  
  


• 
  

  History of primary or acquired immunodeficiency states, including leukemia, lymphomas of any type, other malignant neoplasms affecting the bone marrow or lymphatic system, or clinical manifestations of HIV infection (e.g., AIDS).^{1 6 20 23} (See Individuals with Altered Immunocompetence under Cautions.)

  
  


• 
  

  Immunosuppressive therapy.^{1 6} (See Specific Drugs under Interactions.)

  
  


• 
  

  Pregnancy or possible pregnancy.^{1 6 20} (See Pregnancy under Cautions.)

  
  

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic reactions, reported.¹

As with any vaccine, have appropriate medical treatment (e.g., epinephrine injection 1:1000) readily available in case an anaphylactic/anaphylactoid reaction occurs.¹

Gelatin Allergy

Contains hydrolyzed porcine gelatin (15.58 mg) as a stabilizer.^{1 6} Consider possibility of allergic reactions in individuals sensitive to gelatin.⁸

Neomycin Allergy

Contains trace amounts of neomycin sulfate.^{1 6}

Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis.^{6 8}

Manufacturer and ACIP state do not use in those with history of anaphylactic/anaphylactoid reaction to neomycin, but neomycin allergy manifested as contact dermatitis is not a contraindication.^{1 6 8}

Individuals with Altered Immunocompetence

Because zoster vaccine contains live, attenuated virus, it should not be used in individuals with altered immunocompetence, including those with primary or acquired immunodeficiencies or those receiving immunosuppressive therapy.^{1 6 20}

Not recommended for HIV-infected individuals.^{6 23} ACIP, AAFP, ACOG, and ACP state the vaccine is contraindicated in HIV-infected individuals with CD4⁺ T-cell counts ≤200/mm³ or ≤15% of total lymphocytes.^{6 20}

Risk for herpes zoster and its clinical complications is much greater among immunocompromised individuals than immunocompetent individuals.⁶ Review vaccination status of all immunocompetent individuals ≥60 years of age, particularly those who may be anticipating initiation of immunosuppressive therapy or have diseases that may lead to immunodeficiency.⁶ Those without previous zoster vaccination should receive a single dose of zoster vaccine at the first possible health-care visit while immunity is intact.⁶

Transmission of Vaccine Virus

Zoster vaccine contains live, attenuated virus.¹ Transmission of vaccine virus may occur rarely between vaccinees and susceptible contacts.^{1 6}

Transmission of zoster vaccine virus has not been documented to date; however, transmission of Oka/Merck strain of VZV has been reported rarely following administration of varicella vaccine, usually only when vaccine recipient developed a varicella-like rash.⁶

Weigh risk of possible vaccine virus transmission against risk of developing natural zoster infection that could be transmitted to susceptible contacts.^{1 6}

Primary Varicella Disease

Not indicated for prevention of primary varicella infection (chickenpox).¹

Limitations of Vaccine Effectiveness

Does not prevent herpes zoster in all vaccine recipients.^{1 2} In those who develop herpes zoster, duration of pain and discomfort may be reduced.^{1 2}

May be less effective in those ≥70 years of age than in those 60–69 years of age.^{1 2}

Duration of Immunity

Duration of protection against herpes zoster following a single dose of zoster vaccine and need for revaccination or additional (booster) doses not fully determined.¹ Data to date indicate the duration of protection is at least 4 years.^{1 6}

Concomitant Illness

Defer vaccination in patients with active untreated tuberculosis.¹

A decision to administer or delay vaccination in an individual with a current or recent acute illness depends on the severity of symptoms and etiology of the illness.^{1 6 8} Manufacturer suggests that vaccination be deferred in individuals with acute illness in the presence of fever.¹

ACIP states zoster vaccine may be administered to age-appropriate adults with minor acute illnesses such as diarrhea or mild upper respiratory tract infection (with or without fever), but defer vaccination in those with moderate or severe acute illness (with or without fever).^{6 8}

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency^{8 21} and reduced immune response in vaccinees.⁸

Do not administer zoster vaccine that has been mishandled or has not been stored at the recommended temperature.^{1 8 21} (See Storage under Stability.)

Protect the vaccine from light at all times;^{1 6 8 21} exposure to light may inactivate the vaccine virus.²¹

Avoid freezing or exposing the diluent supplied by the manufacturer to freezing temperatures;²¹ diluent may be refrigerated or stored at room temperature.^{1 6 8 21} (See Storage under Stability.)

Discard any reconstituted vaccine not used within 30 minutes; do not freeze.^{1 6 21} (See Storage under Stability.)

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.⁸ If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether the vaccine is usable.^{8 21}

Specific Populations

Pregnancy

Category C.¹

Not indicated in women of childbearing age; do not administer to pregnant women.^{1 6} Naturally occurring VZV infection can cause fetal harm.^{1 6 7}

Inform vaccinees of the theoretical risk of transmitting the attenuated vaccine virus to varicella-susceptible individuals, including pregnant women who have not had chickenpox.¹ (See Transmission of Vaccine Virus under Cautions.)

Any exposure to zoster vaccine that occurs during pregnancy should be reported to the pregnancy registry at 800-986-8999.^{1 6}

Lactation

Not indicated in nursing women.¹

Not known whether naturally occurring VZV is distributed into milk.¹ Because some viruses are distributed into milk, use caution in nursing women.¹

ACIP states that antigens contained in most live vaccines, including varicella vaccine, are not distributed into milk.⁶ Therefore, breast-feeding is not a contraindication for zoster vaccine.⁶

Pediatric Use

Not indicated in children and adolescents.¹

Geriatric Use

Safety and efficacy established only in adults ≥60 years of age.^{1 6} Median age of individuals enrolled in clinical studies was 69 years.¹

Common Adverse Effects

Headache, injection site reactions (erythema, pain/tenderness, swelling, pruritus, warmth, hematoma).^{1 6}

Interactions for Zoster Vaccine Live

Other Vaccines

Simultaneous administration with other age-appropriate vaccines or toxoids during the same health-care visit (using different syringes and different injection sites) generally is not expected to affect immunologic responses or adverse reactions to any of the vaccines.⁶ However, if another parenteral live vaccine is indicated in a patient receiving zoster vaccine, the vaccines should either be administered on the same day or at least 4 weeks apart.⁶

Specific Drugs

Drug	Interaction	Comments
Antiviral agents active against Herpesviruses (e.g., acyclovir, famciclovir, valacyclovir)	Data not available to date regarding use of zoster vaccine in patients receiving antiviral agents active against VZV1 7 13 16 These antiviral agents may interfere with replication of the live, attenuated VZV contained in zoster vaccine6	Antiviral agents active against VZV should be discontinued at least 24 hours before administration of zoster vaccine, if possible, and should not be used for at least 14 days after vaccination6
Blood products (e.g., whole blood, packed RBCs, plasma)	Levels of anti-VZV contained in blood or blood products are similar to levels found in individuals with a history of varicella6	May be administered simultaneously with or at any time before or after blood or other antibody-containing blood products6
Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation)	Use of zoster vaccine in individuals receiving immunosuppressive agents may result in disseminated disease1	Manufacturer states that zoster vaccine is contraindicated in individuals receiving immunosuppressive agents1 ACIP states zoster vaccine should be administered at least 14 days before initiation of immunosuppressive therapy; some experts advise waiting 1 month after zoster vaccination before initiating such therapy, if possible6
Influenza vaccine	Parenteral inactivated influenza vaccine: Studies using seasonal parenteral inactivated influenza vaccine indicated concomitant administration with zoster vaccine in adults ≥60 years of age results in antibody responses similar to those reported when the vaccines are administered 4 weeks apart 1 6 22	Parenteral inactivated influenza vaccine: May be administered concurrently (using different syringes and different injection sites)1 6 22
Pneumococcal vaccine	Study using pneumococcal 23-valent vaccine (PPSV23; Pneumovax 23) indicated concomitant administration of zoster vaccine in adults ≥60 years of age results in a significantly reduced VZV antibody response similar to that reported when the vaccines are administered 4 weeks apart1 25	Do not administer concurrently with PPSV23 (Pneumovax 23)1 25

Stability

Storage

Parenteral

For Injection, for Sub-Q Use

To maintain potency, keep lyophilized zoster vaccine frozen at -15°C or colder and protect from light during shipment and storage.^{1 6 8}

After delivery, keep lyophilized zoster vaccine frozen at -15°C or colder and protect from light; any freezer (e.g., frost-free) that reliably maintains an average temperature of -15°C or colder and has a separate sealed freezer door is acceptable.^{1 6 8}

When optimal handling conditions are not feasible (e.g., during transportation), the lyophilized vaccine may be stored for ≤72 hours at 2–8°C;¹ discard the refrigerated vaccine if it has not been used within 72 hours after removal from storage at -15°C or colder.¹

Store vial containing the diluent supplied by the manufacturer separately either at room temperature (20–25°C) or in a refrigerator (2–8°C).^{1 6 8 17}

Contact the manufacturer at 800-637-2590 for information regarding vaccine stability under conditions other than those recommended.^{1 6}

Use immediately following reconstitution; discard reconstituted vaccine if not used within 30 minutes.^{1 6 21} Do not freeze.^{1 21}

Zoster vaccine does not contain thimerosal or any other preservatives.^{1 6}

ActionsActions

• 
  

  Zoster vaccine is a lyophilized preparation containing live, attenuated VZV of the Oka/Merck strain.^{1 2 3 4 6 15}

  
  


• 
  

  Vaccination with a single dose of zoster vaccine boosts active immunity to VZV, thereby reducing reactivation of VZV and development of herpes zoster and complications of the disease.^{1 2 3 4 6 15}

  
  


• 
  

  Contains same antigen as varicella vaccine (Varivax); however, zoster vaccine is about 14 times more potent than varicella vaccine.^{6 9 10 12}

  
  


• 
  

  The higher potency of varicella antigen contained in zoster vaccine is required to elicit a clinically important increase in cell-mediated immunity to VZV in older adults.^{2 3}

  
  


• 
  

  Herpes zoster (shingles, zoster) and varicella (chickenpox) are distinct clinical entities caused by the same virus, VZV.^{3 6 7 13 16} During primary infection, VZV causes chickenpox; the virus invades sensory neurons and becomes latent in sensory nerve ganglia, establishing a source of potential secondary infection.^{1 2 3 6 7 13 15 16}

  
  


• 
  

  Herpes zoster is characterized by unilateral, painful, vesicular cutaneous eruption with a dermatomal distribution.^{1 2 6 13 15 16} Pain may occur during the prodrome, the acute eruptive phase, and the postherpetic phase of the infection (PHN).^{1 2 6 13 16} Serious complications of the disease (e.g., scarring, bacterial superinfection, allodynia, cranial and motor neuron palsies, pneumonia, encephalitis, visual impairment, hearing loss, death) may occur.^{1 6 13 15 16}

  
  


• 
  

  A single dose of zoster vaccine in adults ≥60 years of age boosts VZV antibody levels almost twofold.¹

  
  


• 
  

  Minimum antibody titer that correlates with protection against herpes zoster not established.^{1 6 15}

  
  

Advice to Patients

• 
  

  Provide copy of manufacturer’s patient information.^{1 19} Prior to administration of the vaccine dose, also provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient’s legal representative (VISs are available at ).²⁴

  
  


• 
  

  Advise patient of the risks and benefits of vaccination with zoster vaccine.^{1 19}

  
  


• 
  

  Advise patient that they should not receive zoster vaccine if they have a history of anaphylactic/anaphylactoid reactions to any of its ingredients (e.g., gelatin, neomycin).^{1 19}

  
  


• 
  

  Advise patient that they should not receive zoster vaccine if they have a disease that weakens the immune system (e.g., leukemia, lymphoma, HIV/AIDS), are receiving treatment that may weaken the immune system (e.g., cancer treatment with radiation or drugs, corticosteroids), or have active, untreated tuberculosis.^{1 19}

  
  


• 
  

  Advise patient that zoster vaccine may not provide protection against herpes zoster in all vaccinees.^{1 19}

  
  


• 
  

  Advise patient that zoster vaccine can prevent shingles (not chickenpox) and cannot be used to treat shingles once the condition develops.^{1 19}

  
  


• 
  

  Advise patient of the theoretical risk of transmitting the vaccine virus to varicella-susceptible individuals, including pregnant women who have not had chickenpox.^{1 19}

  
  


• 
  

  Importance of informing clinicians if patients had allergic reactions to another vaccine or if they expect to be in close contact with neonates, pregnant women who have not had chickenpox or been vaccinated against chickenpox, or individuals with a weakened immune system.¹⁹

  
  


• 
  

  Importance of contacting clinicians if a hypersensitivity reaction (difficulty breathing, hoarseness, wheezing, hives, paleness, weakness, fast heart beat, dizziness) or other moderate or severe reaction (high fever, weakness, behavior changes) occurs following the vaccine dose.^{1 19} Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or .^{1 6 19}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 19} Importance of avoiding pregnancy for 3 months following vaccination.¹ If any exposure to zoster vaccine occurs during pregnancy, vaccinees and their clinicians are encouraged to contact the pregnancy registry at 800-986-8999.^{1 19}

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Zoster Vaccine Live

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, for subcutaneous use	≥19,400 plaque-forming units (PFU) of Oka/Merck strain of varicella zoster virus per 0.65 mL	Zostavax	Merck,

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck & Co. Zostavax (zoster vaccine live suspension for subcutaneous injection) prescribing information. Whitehouse Station, NJ; 2009 Dec.

2. Oxman MN, Levin MJ, Johnson GR et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005; 352:2271-84. [PubMed 15930418]

3. Arvin A. Aging, immunity, and the varicella-zoster virus. N Engl J Med. 2005; 352:2266-7. [PubMed 15930416]

4. Gilden DH. Varicella-zoster virus vaccine--grown-ups need it, too. N Engl J Med. 2005; 352:2344-6. [PubMed 15930426]

5. Anon. Herpes zoster vaccine (zostavax). Med Lett Drugs Ther. 2006; 48:73-4. [PubMed 16977285]

6. Centers for Disease Control and Prevention. Prevention of herpes zoster. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008; 57(RR-5):1-30.

7. Whitley RJ. Varicella-Zoster Virus. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 6th ed. New York: Churchill Livingstone; 2005:1780-6.

8. Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006; 55(RR-15):1-47.

9. Supplementary Appendix to Oxman MN, Levin MJ, Johnson GR et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005; 352:2271-84. [PubMed 15930418]

10. Merck & Co. Varivax (varicella virus vaccine live) prescribing information. Whitehouse Station, NJ; 2009 Jun.

12. Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007; 56(RR-4):1-40.

13. Gnann JW, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. 2002; 347:340-5. [PubMed 12151472]

14. Centers for Disease Control and Prevention. CDC’s advisory committee recommends “shingles” vaccination. 2006 Oct 26. Press release. From CDC website.

15. Hambleton S, Gershon AA. Preventing varicella-zoster disease. Clin Microbiol Rev. 2005; 18:70-80. [PubMed 15653819]

16. Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the management of herpes zoster. Clin Infect Dis. 2007; 44:S1-S26. [PubMed 17143845]

17. Merck & Co. North Wales, PA: Personal communication.

18. A phase III clinical trial to study the safety, tolerability and immunogenicity of zoster vaccine live (Oka/Merck) in subjects with a history of herpes zoster. From ClinicalTrials.gov web site. Accessed 2007 Jan 8.

19. Merck & Co. Zostavax (zoster vaccine live) patient information. Whitehouse Station, NJ; 2008 Apr.

20. Centers for Disease Control and Prevention. Recommended adult immunization schedule—United States, 2010. MMWR Morb Mortal Wkly Rep. 2010; 59:.

21. Centers for Disease Control and Prevention. Vaccine management: recommendations for storage and handling of selected biologicals. 2007 Nov. From CDC website.

22. Kerzner B, Murray AV, Cheng E et al. Safety and immunogenicity profile of the concomitant administration of zostavax and inactivated influenza vaccine in adults aged 50 and older. J Am Geriatr Soc. 2007; 55:1499-507. [PubMed 17908055]

23. US Department of Health and Human Services (DHHS). Recommended immunizations for HIV positive adults. From the DHHS HIV/AIDS Information Services (AIDSinfo) website. Accessed 2009 Oct 29.

24. Centers for Disease Control and Prevention. Shingles vaccine information statement. 2009 Oct 6. From CDC website.

25. Macintyre CR, Egerton T, McCaughey M et al. Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old. Hum Vaccin. 2010; 6:894-902. [PubMed 20980796]

More Zoster Vaccine Live resources

• Zoster Vaccine Live Side Effects (in more detail)
• Zoster Vaccine Live Use in Pregnancy & Breastfeeding
• Zoster Vaccine Live Drug Interactions
• Zoster Vaccine Live Support Group
• 4 Reviews for Zoster Live - Add your own review/rating

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Compare Zoster Vaccine Live with other medications

• Herpes Zoster, Prophylaxis

Thrombate III

antithrombin iii

Dosage Form: injection

DESCRIPTION

Antithrombin III (Human), Thrombate III® is a sterile, nonpyrogenic, stable, lyophilized preparation of puriï¬ed human antithrombin III.

Thrombate III is prepared from pooled units of human plasma from normal donors by modiï¬cations and reï¬nements of the cold ethanol method of Cohn.1 When reconstituted with Sterile Water for Injection, USP, Thrombate III has a pH of 6.0–7.5, a sodium content of 110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M, and a heparin content of not more than 0.1 IU heparin/IU AT­-III. Thrombate III contains no preservative and must be administered by the intravenous route. In addition, Thrombate III has been heat­-treated in solution at 60°C ±0.5°C for not less than 10 hours.

Each vial of Thrombate III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation.

The manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.24­-27

An individual production step in the Thrombate III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 logs). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

CLINICAL PHARMACOLOGY

Antithrombin III (AT-­III), an alpha2­-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL2,3 and is the major plasma inhibitor of thrombin.4 Inactivation of thrombin by AT-­III occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on AT-­III.4 AT-­III is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.4

The neutralization rate of serine proteases by AT­-III proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin.4 As the therapeutic antithrombotic effect in vivo of heparin is mediated by AT­-III, heparin is ineffective in the absence or near absence of AT­-III.4–8

The prevalence of the hereditary deï¬ciency of AT­-III is estimated to be one per 2000 to 5000 in the general population.4–7 The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with AT-­III levels of 40%–60% of normal.7 These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary antithrombin III (AT-­III) deï¬ciency during pregnancy has been reported to be 70%, and several studies of the beneï¬cial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deï¬ciency have been reported.9–11 In many cases, however, no precipitating factor can be identiï¬ed for venous thrombosis or pulmonary embolism.7 Greater than 85% of individuals with hereditary AT-­III deï¬ciency have had at least one thrombotic episode by the age of 50 years.7 In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals.7 In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of AT-­III, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals.6,7

In clinical studies of Thrombate III conducted in 10 asymptomatic subjects with hereditary deï¬ciency of AT-­III, the mean in vivo recovery of AT-­III was 1.6% per unit per kg administered based on immunologic AT-­III assays, and 1.4% per unit per kg administered based on functional AT-­III assays.12 The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half­-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of AT-­III.12 These values are similar to the half­life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days.13–15

In clinical studies of Thrombate III, none of the 13 patients with hereditary AT­-III deï¬ciency and histories of thromboembolism treated prophylactically on 16 separate occasions with Thrombate III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures and all 5 deliveries. Eight patients with hereditary AT-­III deï¬ciency were treated therapeutically with Thrombate III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with Thrombate III reversed heparin resistance in two patients with hereditary AT-­III deï¬ciency being treated for thrombosis or thromboembolism.

During clinical investigation of Thrombate III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving Thrombate III, became antibody positive to human immunodeï¬ciency virus (HIV­-1). None of 14 subjects monitored for ≥ 3 months demonstrated any evidence of hepatitis, either non­-A, non­-B hepatitis or hepatitis B.

INDICATIONS AND USAGE SECTION

Thrombate III is indicated for the treatment of patients with hereditary antithrombin III deï¬ciency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

Subjects with AT-­III deï¬ciency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease.

The diagnosis of hereditary antithrombin III (AT-­III) deï¬ciency should be based on a clear family history of venous thrombosis as well as decreased plasma AT-­III levels, and the exclusion of acquired deï¬ciency.

AT-­III in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary AT-­III deï¬ciencies.16

The AT­-III level in neonates of parents with hereditary AT-­III deï¬ciency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deï¬ciency, has been reported.)17

Plasma levels of AT-­III are lower in neonates than adults, averaging approximately 60% in normal term infants.18,19 AT­-III levels in premature infants may be much lower.18,19 Low plasma AT-­III levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deï¬ciency. It is recommended that testing and treatment with Thrombate III of neonates be discussed with an expert on coagulation.11

CONTRAINDICATIONS

None known.

WARNINGS SECTION

Thrombate III is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically, the Creutzfeldt­-Jakob (CJD) agent that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1800­-520-­2807]

The physician should discuss the risks and beneï¬ts of this product with the patient, before prescribing or administering it to a patient.

The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-­III deï¬ciency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III.

PRECAUTIONS

General

1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.


2. Administer only by the intravenous route.


3. Thrombate III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions.


4. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with  blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.

Place needles in sharps container after single use. Discard all equipment including any reconstituted Thrombate III product in accordance with biohazard procedures.

The diagnosis of hereditary antithrombin III (AT-­III) deï¬ciency should be based on a clear family history of venous thrombosis as well as decreased plasma AT-­III levels, and the exclusion of acquired deï¬ciency.

Laboratory Tests

It is recommended that AT-­III plasma levels be monitored during the treatment period. Functional levels of AT­-III in plasma may be measured by amidolytic assays using chromogenic substrates or by clotting assays.

Drug Interactions

The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT­-III deï¬ciency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Thrombate III. It is not known whether Thrombate III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established. The AT­-III level in neonates of parents with hereditary AT-­III deï¬ciency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deï¬ciency, has been reported.)17

Plasma levels of AT-­III are lower in neonates than adults, averaging approximately 60% in normal term infants.18,19 AT-­III levels in premature infants may be much lower.18,19 Low plasma AT-­III levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deï¬ciency. It is recommended that testing and treatment with Thrombate III of neonates be discussed with an expert on coagulation.11

Adverse Reactions

In clinical studies involving Thrombate III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were dizziness (7), chest tightness (3), nausea (3), foul taste in mouth (3), chills (2), cramps (2), shortness of breath (1), chest pain (1), ï¬lm over eye (1), light­-headedness (1), bowel fullness (1), hives (1), fever (1), and oozing and hematoma formation (1). If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate.

DOSAGE AND ADMINISTRATION

Each bottle of Thrombate III has the functional activity, in international units (IU), stated on the label of the bottle. The potency assignment has been determined with a standard calibrated against a World Health Organization antithrombin III reference preparation.

Dosage should be determined on an individual basis based on the pre­therapy plasma antithrombin III (AT-­III) level, in order to increase plasma AT­-III levels to the level found in normal human plasma (100%). Dosage of Thrombate III can be calculated from the following formula:                                        

                               

                                [desired-­baseline AT-­III level*] X weight (kg)

units required (IU) =  _________________________________________ 

                                                        1.4

*expressed as % normal level based on functional AT-­III assay

The above formula is based on an expected incremental in vivo recovery above baseline levels for Antithrombin III (Human), Thrombate III®of 1.4% per IU per kg administered.12 Thus, if a 70 kg individual has a baseline AT–III level of 57%, in order to increase plasma AT-­III to 120%, the initial Thrombate III dose would be [(120–57) X70]/1.4 = 3150 IU total.

However, recovery may vary, and initially levels should be drawn at baseline and 20 minutes postinfusion. Subsequent doses can be calculated based on the recovery of the ï¬rst dose. These recommendations are intended only as a guide for therapy. The exact loading dose and maintenance intervals should be individualized for each patient.

It is recommended that following an initial dose of Thrombate III, plasma levels of AT­-III be initially monitored at least every 12 hours and before the next infusion of Thrombate III to maintain plasma AT-­III levels greater than 80%. In some situations, e.g., following surgery,20 hemorrhage or acute thrombosis, and during intravenous heparin administration,13,21–23 the half-­life of Antithrombin III (Human) has been reported to be shortened. In such conditions, plasma AT-­III levels should be monitored more frequently, and Thrombate III administered as necessary.

When an infusion of Thrombate III is indicated for a patient with hereditary deï¬ciency to control an acute thrombotic episode or prevent thrombosis following surgical or obstetrical procedures, it is desirable to raise the AT­-III level to normal and maintain this level for 2 to 8 days, depending on the indication for treatment, type and extent of surgery, patient’s medical condition, past history and physician’s judgment. Concomitant administration of heparin in each of these situations should be based on the medical judgment of the physician.

As a general recommendation, the following therapeutic program may be utilized as a starting program for treatment, modifying the program based on the actual plasma AT­-III levels achieved:

a)An initial loading dose of Thrombate III calculated to elevate the plasma AT-­III level to 120%, assuming an expected rise over the baseline plasma AT­-III level of 1.4% (functional activity) per IU per kg of Thrombate III administered. Thus, if an individual has a baseline AT­-III level of 57%, the initial Thrombate III dose would be (120–57)/1.4 = 45 IU/kg.

b)Measure preinfusion and 20 minutes postinfusion (peak) plasma antithrombin III levels following the initial loading dose, plasma antithrombin III level after 12 hours, then preceding the next infusion (trough level). Subsequently measure antithrombin III levels preceding and 20 minutes after each infusion until predictable peak and trough levels have been achieved, generally between 80%–120%. Plasma levels between 80%–120% may be maintained by administration of maintenance doses of 60% of the initial loading dose, administered every 24 hours. Adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma AT-­III levels achieved.

The above recommendations for dosing are provided as a general guideline for therapy only. The exact loading and maintenance dosages and dosing intervals should be individualized for each subject, based on the individual clinical conditions, response to therapy, and actual plasma AT-­III levels achieved. In some situations, e.g., following surgery,20 with hemorrhage or acute thrombosis and during intravenous heparin administration,13,21–23 in vivo survival of infused Thrombate III has been reported to be shortened, resulting in the need to administer Thrombate III more frequently.

Antithrombin III (Human), Thrombate III should be reconstituted with Sterile Water for Injection, USP and brought to room temperature prior to administration. Thrombate III should be ï¬ltered through a sterile ï¬lter needle as supplied in the package prior to use, and should be administered within 3 hours following reconstitution. Thrombate III may be infused over 10–20 minutes. Thrombate III must be administered intravenously. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution

Vacuum Transfer

Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into contact with the product to be administered via the intravenous route should not come in contact with any nonsterile surface. Any contaminated needles should be discarded by placing in a puncture-­proof container and new equipment should be used.

1. After removing all items from the box, warm the sterile water (diluent) to room temperature (25°C, 77°F).


2. Remove shrink band from product vial. If the shrink band is absent or shows signs of tampering, do not use the product and notify Talecris Biotherapeutics, Inc. immediately.


3. Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the stopper.


4. Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed needle into the diluent vial to the hub (Fig. B).


5. Carefully grip the sheath of the other end of the transfer needle and twist to remove it.


6. Invert the diluent vial and insert the attached needle into the concentrate vial at a 45°angle (Fig. C). This will direct the stream of diluent against the wall of the concentrate vial and minimize foaming. The vacuum will draw the diluent into the concentrate vial.*


7. When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).


8. Immediately after adding the diluent, swirl continuously until completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming. The vial should then be visually inspected for particulate matter and discoloration prior to administration.


9. Clean the top of the vial of reconstituted Thrombate III again with alcohol swab and let surface dry.


10. Attach the ï¬lter needle (from the package) to sterile syringe. Withdraw the Thrombate III solution into the syringe through the ï¬lter needle (Fig. F).


11. Remove the ï¬lter needle from the syringe and replace with an appropriate injection or butterfly needle for administration. Discard ï¬lter needle into a puncture­proof container.


12. If the same patient is using more than one vial of Thrombate III, the contents of multiple vials may be drawn into the same syringe through the ï¬lter needles provided.

*If vacuum is lost in the concentrate vial, use a sterile syringe to remove the sterile water from the diluent vial and inject it into the concentrate vial, directing the stream of fluid against the wall of the vial.

A number of factors could reduce the efï¬cacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product is stored properly, that the directions are followed carefully during use, and that the risk of transmitting viruses is carefully weighed before the product is prescribed.

Rate of Administration

The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.

HOW SUPPLIED

Thrombate III is supplied in the following single use vials with the potency in international units stated on the label of each vial. A suitable volume of Sterile Water for Injection, USP, a sterile double­ended transfer needle, and a sterile ï¬lter needle are provided.

NDC Number	Approximate Antithrombin III Potency	Diluent
13533-603-20	500 IU	10 mL

STORAGE

Thrombate III should be stored at temperatures not to exceed 25°C (77°F). Freezing should be avoided as breakage of the diluent bottle might occur.

CAUTION

Rx only


U.S. federal law prohibits dispensing without prescription.

REFERENCES

1. Cohn EJ, Strong LE, Hughes WL Jr, et al: Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 68(3):459-­75, 1946.


2. Rosenberg RD, Bauer KA, Marcum JA: Antithrombin III “the heparin-­antithrombin system.” Rev Hematol 2:351­-416, 1986.


3. Murano G, Williams L, Miller-­Andersson M: Some properties of antithrombin-­III and its concentration in human plasma. Thromb Res 18(1­2):259­-62, 1980.


4. Rosenberg RD: Action and interactions of antithrombin and heparin. N Engl J Med 292(3):146­-51, 1975.


5. Winter JH, Fenech A, Ridley W, et al: Familial antithrombin III deï¬ciency. Q J Med 51(204):373-­95, 1982.


6. Marciniak E, Farley CH, DeSimone PA: Familial thrombosis due to antithrombin III deï¬ciency. Blood 43(2):219­31, 1974.


7. Thaler E, Lechner K: Antithrombin III deï¬ciency and thromboembolism. Clin Haematol 10(2):369­-90, 1981.


8. Blauhut B, Necek S, Kramar H, et al: Activity of antithrombin III and effect of heparin on coagulation in shock. Thromb Res 19(6):775­-82, 1980.


9. Samson D, Stirling Y, Woolf L, et al: Management of planned pregnancy in a patient with congenital antithrombin III deï¬ciency. Br J Haematol 56(2):243-­9, 1984.


10. Brandt P: Observations during the treatment of antithrombin-­III deï¬cient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion. Thromb Res 22(1­-2):15­-24, 1981.


11. Hellgren M, Tengborn L, Abildgaard U: Pregnancy in women with congenital antithrombin III deï¬ciency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 14(2):127-­41, 1982.


12. Schwartz RS, Bauer KA, Rosenberg RD, et al: Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deï¬ciency of antithrombin. Am J Med 87 (Suppl 3B): 53S­-60S, 1989.


13. Collen D, Schetz J, de Cock F, et al: Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest 7(1):27­-35, 1977.


14. Knot EAR, de Jong E, ten Cate JW, et al: Puriï¬ed radiolabeled antithrombin III metabolism in three families with hereditary AT III deï¬ciency: application of a three-­compartment model. Blood 67(1):93-­8, 1986.


15. Tengborn L, Frohm B, Nilsson LE, et al: Antithrombin III concentrate: its catabolism in health and in antithrombin III deï¬ciency. Scand J Clin Lab Invest 41(5):469­-77, 1981.


16. Sas G, Blasko G, Banhegyi D, et al: Abnormal antithrombin III (antithrombin III “Budapest”) as a cause of familial thrombophilia. Thromb Diath Haemorrh 32(1):105­-15, 1974.


17. Bjarke B, Herin P, Blomback M: Neonatal aortic thrombosis. A possible clinical manifestation of congenital antithrombin III deï¬ciency. Acta Paediatr Scand 63:297­-301, 1974.


18. Hathaway WE, Bonnar J: Perinatal coagulation. New York, Grune & Stratton, 1978, p.68.


19. Peters M, Jansen E, ten Cate JW, et al: Neonatal antithrombin III. Br J Haematol 58(4):579­-87, 1984.


20. Mannucci PM, Boyer C, Wolf M, et al: Treatment of congenital antithrombin III deï¬ciency with concentrates. Br J Haematol 50(3):531­5, 1982.


21. Marciniak E, Gockerman JP: Heparin­induced decrease in circulating antithrombin­III. Lancet 2(8038):581­4, 1977.


22. O’Brien JR, Etherington MD: Effect of heparin and warfarin on antithrombin III. Lancet 2(8050):1232, 1977.


23. Kakkar VV, Bentley PG, Scully MF, et al: Antithrombin III and heparin. Lancet 1(8159):103­-4, 1980.


24. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the puriï¬cation of therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497­-500.


25. Lee DC, Stenland CJ, Miller JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the puriï¬cation of plasma proteins. Transfusion 2001. 41(4):449­-55.


26. Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84(1):77-­89.


27. Cai K, Miller JL, Stenland CJ, et al. Solvent­-dependent precipitation of prion protein. BiochimBiophys Acta 2002. 1597(1):28­-35.

08939599 (Rev. May 2009)


Talecris Biotherapeutics, Inc.

Research Triangle Park,  

NC 27709 USA U.S. License No. 1716

PACKAGE LABEL

NDC 13533-603-20


Antithrombin III

(Human)


Thrombate III®


Heat-Treated   Lyophilized

In Solution           Powder


Talecris Biotherapeutics, Inc.

Research Triangle Park,

NC 27709 USA

U.S. License No. 1716

The risk of transmission of hepatitis and

other viral deseases is present.

The patient and physician should discuss the

risks and benefits of this product.

No Preservative

For Intravenous Administration Only

Sterile - Nonpyrogenic

Reconstitute with 10 mL Sterile Water for

Injection, USP.

Store at temperatures not to exceed 25ºC

(77º F).  Do not freeze.

Dosage and Administration:  Read package

insert.

Rx only

THIS PRODUCT IS PREPARED FROM LARGE POOLS OF

HUMAN PLASMA WHICH MAY CONTAIN THE CAUSATIVE

AGENTS OF HEPATITIS AND OTHER VIRAL DISEASES.  SEE

PACKAGE INSERT WARNINGS


The patient and physician should discuss the risks and benefits of

this product.


The product when reconstituted with 10 mL Sterile Water for

injection, USP, contains 110-210 mEq/L sodium, 110-210 mEq/L

chloride, 0.075-0.125 M alanine, and not more than 0.1 Iu

heparin/IU AT-III.


Administer within 3 hours after reconstitution.


Dosage and Administration:  Read enclosed package insert.


Store at temperature not to exceed 25º C (77º F).  Do not freeze.


If the shrink band is absent or shows any sign of tampering, do not

use the product and notify Talecris Biotherapeutics, Inc.

immediately.


Not Returnable for Credit or Exchange


Rx only


CAUTION:  U.S. federal law prohibits despensing without

prescription

CONTENTS:


One bottle of Thrombate III

10 mL Sterile Water for Injection,

     USP

One sterile filter needle

One sterile double-ended transfer

     needle


No Preservative

For Intravenous

      Administration Only

Sterile-Nonpyrogenic

Thrombate III   antithrombin iii  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 13533-603

Packaging # NDC Package Description Multilevel Packaging 1 13533-603-20 1 KIT In 1 CARTON None

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 VIAL, GLASS   10 mL Part 2 1 VIAL, GLASS   10 mL

Part 1 of 2 ANTITHROMBIN III   antithrombin iii  injection, powder, lyophilized, for solution

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Antithrombin Iii (human) (Antithrombin Iii (human)) Antithrombin Iii (human) 50 [iU]  in 10 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL, GLASS None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103196 12/30/1991

Part 2 of 2 STERILE WATER   water  injection

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength No Active Ingredients Found

Inactive Ingredients Ingredient Name Strength Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL, GLASS None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103196 12/30/1991

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA103196	12/30/1991

Labeler - TALECRIS BIOTHERAPEUTICS, INC. (839731507)

Establishment
Name	Address	ID/FEI	Operations
TALECRIS BIOTHERAPEUTICS HOLDINGS CORP		611019113	MANUFACTURE

Revised: 01/2010TALECRIS BIOTHERAPEUTICS, INC.

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