Stamaril

1. Name Of The Medicinal Product

STAMARIL (or local trade name)

Powder and solvent for suspension for injection in pre-filled syringe.

Yellow fever vaccine (Live).

2. Qualitative And Quantitative Composition

After reconstitution, 1 dose (0.5 ml) contains:

Yellow fever virus¹ 17 D-204 strain (live, attenuated) ........................... not less than 1000 LD₅₀ units²

¹ produced in specified pathogen-free chick embryos

² The statistically determined lethal dose in 50% of animals tested

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for suspension for injection.

The powder is beige to orange beige; the solvent is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

STAMARIL is indicated for active immunization against yellow fever in persons:

• travelling to, passing through or living in an endemic area,

• travelling to any country that requires an International Certificate of Vaccination for entry (which may or may not depend on the previous itinerary).

• handling potentially infectious materials (e.g. laboratory personnel).

See sections 4.2, 4.3 and 4.4 regarding the minimum age for vaccination of children under special circumstances and guidance for vaccination of other specific patient populations.

In order to comply with vaccine regulations and to be officially recognised, yellow fever vaccines must be administered in an approved World Health Organization (WHO) vaccination centre and registered on an International Certificate of Vaccination. This certificate is valid for 10 years from the 10th day after vaccination and immediately after re-vaccination.

4.2 Posology And Method Of Administration

Posology

Primary vaccination

Adults and children aged 9 months and over: A single dose of 0.5 ml of reconstituted vaccine.

Children under 9 months of age: The vaccine must not be given to children less than 6 months old (see section 4.3). Vaccination against yellow fever is not usually recommended in children aged from 6 months up to 9 months except in specific circumstances and in accordance with available official recommendations (see section 4.4), in which case the dose is the same as in older children and adults.

The vaccine should be given at least 10 days before entering an endemic area since protective immunity may not be achieved until at least this time has elapsed.

Elderly

The dose is the same as for adults. However due to a higher risk of yellow fever vaccine-associated severe and potentially fatal disease in persons from 60 years of age, the vaccine should only be given when it is considered that there is a considerable and unavoidable risk of acquiring yellow fever infection (see sections 4.4 and 4.8).

Re-vaccination

Re-vaccination with one dose of 0.5 ml is recommended every 10 years in persons considered to be at risk of exposure.

International Health Regulations require re-vaccination, using the same dose as for primary vaccination, at intervals of 10 years in order to retain a valid certificate.

Method of administration

It is preferable that the vaccine is injected by the subcutaneous route

Intramuscular injection may be performed if this is in accordance with applicable official recommendations.

For intramuscular use the recommended injection sites are the anterolateral aspect of the thigh in the infants and toddlers (6 months up to 2 years of age) and the deltoid muscle in older children and adults.

DO NOT INJECT INTRAVASCULARLY

See section 6.6. for instructions on reconstitution

4.3 Contraindications

• Hypersensitivity reaction to eggs, chicken proteins or to any component of STAMARIL

• Serious hypersensitivity reactions (e.g., anaphylaxis) after a previous dose of any yellow fever vaccine.

• Immunosuppression, whether congenital, idiopathic or as a result of treatment with systemic steroids (greater than the standard dose of topical or inhaled steroids), radiotherapy or cytotoxic drugs.

• History of thymus dysfunction (including thymoma, thymectomy)

• Symptomatic HIV infection

• Asymptomatic HIV infection when accompanied by evidence of impaired immune function (see section 4.4).

• Age less than 6 months (see sections 4.2 and 4.4).

• Current severe febrile illness.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of anaphylaxis or other severe hypersensitivity reaction following administration of the vaccine.

STAMARIL should be administered only to persons who are/will be at risk of infection with yellow fever virus or who must be vaccinated to comply with international health regulations. Before considering administration of yellow fever vaccine, care should be taken to identify those who might be at increased risk of adverse reactions following vaccination (see section 4.3 and below).

Yellow fever vaccine associated neurotropic disease

Very rarely, yellow fever vaccine-associated neurotropic disease (YEL-AND) has been reported following vaccination, with sequelae or with fatal outcome in some cases (see section 4.8). Clinical features have appeared within one month of vaccination and include high fever with headache that may progress to include one or more of the following: confusion, encephalitis/encephalopathy, meningitis, focal neurological deficits, or Guillain Barré syndrome. To date, those affected have been primary vaccinees. The risk appears to be higher in those aged over 60 years, although cases have been also reported in younger persons or following transmission from nursing mothers to the infants.

Yellow fever vaccine-associated viscerotropic disease

Very rarely, yellow fever vaccine-associated viscerotropic disease (YEL-AVD) resembling fulminant infection by wild-type virus has been reported following vaccination (see section 4.8). The clinical presentation may include fever, fatigue, myalgia, headache, hypotension, progressing to one or more of metabolic acidosis, muscle and liver cytolysis, lymphocytopenia and thrombocytopenia, renal failure and respiratory failure. The mortality rate has been around 60%. To date, all cases of YEL-AVD have been in primary vaccinees with onset within 10 days of vaccination. The risk appears to be higher in those aged over 60 years although cases have also been reported in younger persons. Disease of the thymus gland has also been recognised as a potential risk factor (see section 4.3 and section 4.8).

Immunosuppressed persons

STAMARIL must not be administered to immunosuppressed persons (see section 4.3).

If the immunosuppression is temporary, vaccination should be delayed until the immune function has recovered. In patients who have received systemic corticosteroids for 14 days or more, it is advisable to delay vaccination until at least one month after completing the course.

• HIV infection

STAMARIL must not be administrated to persons with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function (see section 4.3). However, there are insufficient data at present to determine the immunological parameters that might differentiate persons who could be safely vaccinated and who might mount a protective immune response from those in whom vaccination could be both hazardous and ineffective. Therefore, if an asymptomatic HIV-infected person cannot avoid travel to an endemic area available official guidance should be taken into account when considering the potential risks and benefits of vaccination.

• Children born to HIV positive mothers

Children aged at least 6 months (see sections 4.2 and 4.3 and below) may be vaccinated if it is confirmed that they are not infected with HIV.

HIV infected children aged at least 6 months who are potentially in need of protection against yellow fever should be referred to a specialist paediatric team for advice on whether or not to vaccinate.

Age

• Children aged 6 to 9 months

STAMARIL must not be administered to children before the age of 6 months (see section 4.3). Children aged from 6 months up to 9 months should only be vaccinated under special circumstances (e.g. during major outbreaks) and on the basis of current official advice.

• Persons aged 60 years and older

Some serious and potentially fatal adverse reactions (including systemic and neurological reactions persisting more than 48 hours, YEL-AVD and YEL-AND) appear to occur at higher frequencies after the age of 60 years. Therefore, the vaccine should only be given to those who have a considerable risk of acquiring yellow fever (see above and section 4.8).

Because intramuscular injection can cause injection site haematoma, STAMARIL should not be given by the intramuscular route to persons with any bleeding disorder, such as haemophilia or thrombocytopenia, or to persons on anticoagulant therapy. The subcutaneous route of administration should be used instead.

Patients with rare hereditary problems of fructose intolerance should not take this vaccine.

Transmission

There are very few reports suggesting that transmission of Yellow Fever vaccine virus may occur from nursing mothers, who received Yellow Fever vaccine postpartum, to the infant. Following transmission the infants may develop yellow fever vaccine associated neurotropic disease (YEL-AND) from which the infants recover (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

STAMARIL must not be mixed with any other vaccine or medicinal product in the same syringe.

If there is a need to administer another injectable vaccine(s) at the same time as STAMARIL each vaccine should be injected into a separate site (and preferably a separate limb).

STAMARIL may be administered at the same time as measles vaccine if this is in accordance with official recommendations.

STAMARIL may be administered at the same time as vaccines containing typhoid Vi capsular polysaccharide and/or inactivated hepatitis A virus.

STAMARIL must not be administered to persons who are receiving immunosuppressant therapy (e.g., cytotoxic agents, systemic steroids, greater than standard dose of topical or inhaled steroids or other agents). See section 4.3.

4.6 Pregnancy And Lactation

Pregnancy

No animal reproduction studies have been conducted with STAMARIL and the potential risk for humans is unknown. Data on a limited number of exposed pregnancies indicate no adverse effects of STAMARIL on pregnancy or the health of the fetus/newborn child. Nevertheless, STAMARIL should be given to pregnant women only when clearly needed and only after careful consideration of the potential risks and benefits.

Lactation

As there is a probable risk of transmission of the vaccine virus strain to the infants from breast-feeding mothers, STAMARIL should not be given to nursing mothers unless when clearly needed such as during an outbreak control, and following an assessment of the risks and benefits (see section 4.4.).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive or use machine have been performed.

4.8 Undesirable Effects

Data from clinical studies

Across clinical studies, the most common adverse reactions occurring after vaccine administration were local reactions, reported in approximately 16% of subjects.

The following adverse events are from one clinical study in which 106 healthy adult subjects received STAMARIL. .

The adverse events are ranked under headings of frequency, using the following convention:

• Very common:

• Common:

• Uncommon:

Nervous system disorders
Very common:	Headache
Gastro-intestinal system disorders
Common:	Nausea, Diarrhoea, Vomiting
Uncommon:	Abdominal pain
Musculo-skeletal and connective tissue disorders
Common:	Myalgia
Uncommon:	Arthralgia
General disorders and administration site conditions
Very common:	Local reactions (including pain, redness, haematoma, induration, swelling)
Common:	Pyrexia, Asthenia

Data from post-marketing experience

The following additional adverse events have been reported during post marketing experience with STAMARIL. They are based on spontaneous reporting therefore the frequencies are unknown.

Blood and lymphatic system disorders

Lymphadenopathy

Immune system disorders

Anaphylaxis, angioedema.

Nervous system disorders

Cases of neurotropic disease (known as YEL-AND), some of which have had a fatal outcome, have been reported following yellow fever vaccination (see section 4.4). YEL-AND may manifest as high fever with headache that may progress to include one or more of confusion, lethargy, encephalitis, encephalopathy and meningitis (see section 4.4).

Other neurological signs and symptoms have been reported and include convulsion, Guillain-Barré syndrome and focal neurological deficits.

Skin and subcutaneous tissue disorders

Rash, Urticaria

General disorders and administration site conditions

Cases of viscerotropic disease (known as YEL-AVD and formerly described as “Febrile Multiple Organ-System Failure”) have been reported following yellow fever vaccination some of which have been fatal (see section 4.4). YEL-AVD may manifest as fever, fatigue, myalgia, headache and hypotension progressing to one or more of metabolic acidosis, muscle and liver cytolysis, lymphocytopenia and thrombocytopenia, renal and respiratory failure.

Additional information on special population

Congenital or acquired immunodeficiency has been identified as a risk factor for neurotropic disease (See sections 4.3 and 4.4).

Age of more than 60 years (see section 4.4) has been identified as a risk factor for YEL-AVD and YEL-AND. A medical history of thymic disease (see sections 4.3 and 4.4) has been identified as a risk factor for YEL-AVD.

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Yellow Fever Vaccine (Live)

ATC code: J07B L1

STAMARIL is a live attenuated yellow fever virus vaccine. As with other live attenuated viral vaccines, there is a sub-clinical infection in healthy recipients that results in the production of specific B and T cells and the appearance of specific circulating antibody.

Protective immunity appears from about 10 days after injection. Although International Health Regulations require re-vaccination at intervals of 10 years in order to retain a valid certificate, some degree of immunity likely persists for more than 10 years.

5.2 Pharmacokinetic Properties

No pharmacokinetic studies have been performed.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

Lactose

Sorbitol E420

L-histidine hydrochloride

L-alanine

Sodium chloride

Potassium chloride

Disodium phosphate

Monopotassium phosphate

Calcium chloride

Magnesium sulphate

Solvent:

Sodium chloride

Water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this vaccine must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

After reconstitution, the medicinal product must be used immediately.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl), and an attached needle and needle-shield (natural rubber or polyisoprene)– pack size of 1, 10 or 20.

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl), and a tip-cap (chlorobromobutyl or styrene - butadiene) – pack size of 1, 10.

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl) and a tip cap (chlorobromobutyl or styrene - butadiene) with 1 or 2 separate needles attached in the blister– pack size of 1 and 10.

Not all pack sizes or presentations may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For syringe without attached needle only: After removing the syringe tip cap, the needle should be firmly placed on the tip of the syringe and secured by rotating a quarter of a turn (90°).

The powder is reconstituted by adding the solvent provided in the pre-filled syringe to the vial. The vial is shaken and, after complete dissolution, the suspension obtained is withdrawn into this same syringe for injection.

Before administration, the reconstituted vaccine should be shaken vigorously.

Use immediately after reconstitution.

After reconstitution the suspension is beige to pink beige.

Contact with disinfectants is to be avoided since they may inactivate the virus.

Any unused product or waste material should be disposed of, preferably by heat inactivation or incineration, in accordance with local requirements.

7. Marketing Authorisation Holder

Sanofi Pasteur MSD Limited

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire SL6 1QP

8. Marketing Authorisation Number(S)

PL 6745/0087

9. Date Of First Authorisation/Renewal Of The Authorisation

03/09/2007

10. Date Of Revision Of The Text

11/2010

Primacor

milrinone lactate

Dosage Form: Injection

200 MCG/ML IN 5% DEXTROSE INJECTION

Primacor Description

Primacor, brand of milrinone lactate injection, is a member of a class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Primacor (milrinone lactate) is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile lactate and has the following structure:

Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and an empirical formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Primacor is available as sterile aqueous solutions of the lactate salt of milrinone for infusion intravenously.

Pre-Mix Flexible Containers:The Flexible Containers provide two ready-to-use dilutions of milrinone in volumes of 100 mL and 200 mL of 5% Dextrose Injection. Each mL contains milrinone lactate equivalent to 200 mcg milrinone. The nominal concentration of lactic acid is 0.282 mg/mL. Each mL also contains 49.4 mg dextrose, anhydrous, USP. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The flexible plastic container is comprised of polyvinyl chloride with a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the pre-mix solution.

Primacor - Clinical Pharmacology

Primacor is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.

Primacor, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that Primacor is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.

Clinical studies in patients with congestive heart failure have shown that Primacor produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that Primacor produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Primacor also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.

Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL.

In addition to increasing myocardial contractility, Primacor improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation.

The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.

PHARMACOKINETICS

Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, Primacor had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent.

Primacor has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein.

The primary route of excretion of Primacor in man is via the urine. The major urinary excretions of orally administered Primacor in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of Primacor is approximately 0.3 liters/min, indicative of active secretion.

Pharmacodynamics

In patients with heart failure due to depressed myocardial function, Primacor produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with Primacor was accompanied by clinical symptomatic improvement, but the ability of Primacor to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of the initiation of therapy.

In studies in congestive heart failure patients, Primacor when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of Primacor for periods up to 72 hours without evidence of tachyphylaxis.

The duration of therapy should depend upon patient responsiveness.

Primacor has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that Primacor may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with Primacor.

Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.

The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of Primacor on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range.

Indications and Usage for Primacor

Primacor is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving Primacor should be observed closely with appropriate electrocardiographic equipment. The facility for immediate treatment of potential cardiac events, which may include life threatening ventricular arrhythmias, must be available. The majority of experience with intravenous Primacor has been in patients receiving digoxin and diuretics. There is no experience in controlled trials with infusions of Primacor for periods exceeding 48 hours.

Contraindications

Primacor is contraindicated in patients who are hypersensitive to it.

Warnings

Whether given orally or by continuous or intermittent intravenous infusion, Primacor has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with Primacor was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that Primacor given by long-term continuous or intermittent infusion does not carry a similar risk.

The use of Primacor both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving Primacor should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

Precautions

General

Primacor should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.

Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of Primacor and oral Primacor have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving Primacor should be closely monitored during infusion.

Primacor produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.

During therapy with Primacor, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, Primacor should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.

There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (seeADVERSE REACTIONS). Consequently,careful monitoring of the infusion site should be maintainedto avoid possible extravasation.

Use in Acute Myocardial Infarction

No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, Primacor is not recommended in these patients.

Laboratory Tests

Fluid and Electrolytes

Fluid and electrolyte changes and renal function should be carefully monitored during therapy with Primacor. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of Primacor.

Drug Interactions

No untoward clinical manifestations have been observed in limited experience with patients in whom Primacor was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

Chemical Interactions

There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of Primacor. Therefore, furosemide should not be administered in intravenous lines containing Primacor.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Twenty-four months of oral administration of Primacor to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when Primacor was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, Primacor had no effect on male or female fertility at oral doses up to 32 mg/kg/day.

Animal Toxicity

Oral and intravenous administration of toxic dosages of Primacor to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

Pregnancy Category C

Oral administration of Primacor to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Primacor did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Primacor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when Primacor is administered to nursing women, since it is not known whether it is excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in Elderly Patients

There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered Primacor in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of Primacor.

Adverse Reactions

Cardiovascular Effects

In patients receiving Primacor in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of Primacor increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal digoxin levels and catheter insertion. Primacor was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving Primacor. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.

Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.

In the post marketing experience, there have been rare cases of "torsades de pointes" reported.

CNS Effects

Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving Primacor.

Other Effects

Other adverse reactions reported, but not definitely related to the administration of Primacor include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.

Post-Marketing Adverse Event Reports

In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with Primacor:

Isolated spontaneous reports of bronchospasm and anaphylactic shock.

Liver function test abnormalities and skin reactions such as rash.

Administration site conditions: Infusion site reaction.

Overdosage

Doses of Primacor may produce hypotension because of its vasodilator effect. If this occurs, administration of Primacor should be reduced or temporarily discontinued until the patient's condition stabilizes. No specific antidote is known, but general measures for circulatory support should be taken.

Primacor Dosage and Administration

Primacor (milrinone lactate) should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:

LOADING DOSE

50 mcg/kg: Administer slowly over 10 minutes

Note: Primacor Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are for intravenous infusion only and should not be used for a loading dose. Dosage recommendations using a 1mg/mL concentration of milrinone are included for informational purposes only. The loading dose should be administered using a milrinone 1mg/mL vial.

The table below shows the loading dose in milliliters (mL) of milrinone (1mg/mL) by patient body weight (kg).

Loading Dose (mL) Using 1 mg/mL Concentration

Patient Body Weight (kg)
kg	30	40	50	60	70	80	90	100	110	120
mL	1.5	2.0	2.5	3.0	3.5	4.0	4.5	5.0	5.5	6.0

The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (seeMaintenance Dosefor diluents) may simplify the visualization of the injection rate.

MAINTENANCE DOSE

	Infusion Rate	Total Daily Dose (24 Hours)
Minimum	0.375 mcg/kg/min	0.59 mg/kg	Administer as a
Standard	0.50 mcg/kg/min	0.77 mg/kg	continuous
Maximum	0.75 mcg/kg/min	1.13 mg/kg	intravenous infusion

The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.

Note: See"Dosage Adjustment in Renally Impaired Patients."Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.

The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.

Note:Primacor supplied in 100 mL and 200 mL Flexible Containers (200 mcg/mL in 5% Dextrose Injection) need not be diluted prior to use.

Primacor Infusion Rate (mL/hr) Using 200 mcg/mL Concentration

Maintenance Dose	Patient Body Weight (kg)
(mcg/kg/min)	30	40	50	60	70	80	90	100	110	120
0.375	3.4	4.5	5.6	6.8	7.9	9.0	10.1	11.3	12.4	13.5
0.400	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0	13.2	14.4
0.500	4.5	6.0	7.5	9.0	10.5	12.0	13.5	15.0	16.5	18.0
0.600	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0	19.8	21.6
0.700	6.3	8.4	10.5	12.6	14.7	16.8	18.9	21.0	23.1	25.2
0.750	6.8	9.0	11.3	13.5	15.8	18.0	20.3	22.5	24.8	27.0

When administering Primacor (milrinone lactate) by continuous infusion, it is advisable to use a calibrated electronic infusion device.

The Flexible Container has a concentration of milrinone equivalent to 200 mcg/mL in 5% Dextrose Injection. To use the Flexible Container, tear the overwrap at the notch and remove the Pre-Mix solution container. Squeeze the container firmly to check for leaks. Discard the container if leaks are found since the sterility of the product could be affected. Do not add supplementary medication. To prepare the container for administration of Primacor intravenously, use aseptic techniques.

1)

The flow control clamp of the administration set is closed.

2)

The cover of the outlet port at the bottom of the container is removed.

3)

Noting the full directions on the administration set carton, the piercing pin of the set is inserted into the port with a twisting motion until it is firmly seated.

4)

The container is suspended on the hanger.

5)

The drip chamber is squeezed and released to establish the fill level.

6)

The flow control clamp is opened to expel air from the set, and then closed.

7)

The set is attached to the venipuncture device, primed, and if not indwelling, the venipuncture is performed.

8)

The rate of administration is controlled with the flow control clamp. WARNING- DO NOT USE IN SERIES CONNECTIONS. Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.

Dosage Adjustment in Renally Impaired Patients

Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of Primacor. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:

Creatinine Clearance (mL/min/1.73m2)	Infusion Rate (mcg/kg/min)
5	0.20
10	0.23
20	0.28
30	0.33
40	0.38
50	0.43

How is Primacor Supplied

Primacor Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are supplied:

100 mL (200 mcg/mL) NDC 0024-1203-11 in 5% Dextrose Injection single units.

200 mL (200 mcg/mL) NDC 0024-1203-22 in 5% Dextrose Injection single units.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the Flexible Containers be stored at room temperature, 25 C (77 F), however, brief exposure up to 40 C (104 F) does not adversely affect the product.

Manufactured by:

Hospira Inc.

Lake Forest, IL 60045

Manufactured for:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

Revised March 2007B

©2007 sanofi-aventis U.S. LLC

Primacor  milrinone lactate  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0024-1203 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength milrinone lactate (milrinone) Active 200 MICROGRAM  In 1 MILLILITER Dextrose, Anhydrous Inactive 49.4 MILLIGRAM  In 1 MILLILITER lactic acid Inactive 0.282 MILLIGRAM  In 1 MILLILITER Water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0024-1203-01 100 mL (MILLILITER) In 1 CONTAINER None 2 0024-1203-02 200 mL (MILLILITER) In 1 CONTAINER None

Revised: 02/2008sanofi-aventis U.S. LLC

More Primacor resources

• Primacor Side Effects (in more detail)
• Primacor Dosage
• Primacor Use in Pregnancy & Breastfeeding
• Primacor Drug Interactions
• Primacor Support Group
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• Primacor Concise Consumer Information (Cerner Multum)


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• Heart Failure

Viridal Duo 40 micrograms / ml,Powder and Solvent for Solution for Injection.

1. Name Of The Medicinal Product

Viridal Duo 40 microgram/ml, Powder and Solvent for Solution for Injection

2. Qualitative And Quantitative Composition

Alprostadil 40 micrograms (used as a 1:1 clathrate complex with alfadex)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and Solvent for Solution for Injection.

The powder is odourless and white, and the isotonic sodium chloride solution is clear. The powder dissolves immediately to yield a clear solution.

4. Clinical Particulars

4.1 Therapeutic Indications

As an adjunct to the diagnostic evaluation of erectile dysfunction in adult males.

Treatment of erectile dysfunction in adult males.

4.2 Posology And Method Of Administration

The drug solution should be prepared shortly before the injection.

Prior to injection the needle should be screwed onto the tip of the injector. After disinfecting the tip of the cartridge with one of the alcohol swabs, the cartridge should then be inserted into the injector. By screwing the thread part clockwise, the cartridge is fixed in the injector. Then, the dry substance, which is inside the front chamber of the cartridge, is reconstituted with 1 ml sterile sodium chloride solution 0.9% in the bottom chamber. While holding the device in a vertical position with the needle upwards, the thread part should be screwed slowly until it will not go any further. The solvent will by-pass the upper stopper into the front chamber and dissolve the dry substance within a few seconds. As soon as the dry substance is reconstituted, the larger external and the smaller inner protective cap have to be removed from the needle. The air should then be expelled out of the cartridge and the prescribed dose adjusted precisely.

Unused solution must be discarded immediately.

Viridal Duo is injected into either the right or the left cavernous body of the penile shaft. Once the needle is in the cavernous body, the injection should be done within 5 to 10 seconds and is very easy without much resistance if the needle is in the correct position.

The development of an erection will start approximately 5 – 15 minutes after the injection.

Dosage for injection in the clinic

Injections for diagnostic evaluation and dose titration must be performed by the attending physician. He will determine an individual dose suitable to produce an erectile response for diagnostic purposes.

The recommended starting dose is 2.5 mcg Viridal Duo in patients with primary psychogenic or neurogenic origin of erectile dysfunction. In all other patients with erectile dysfunction 5 mcg Viridal Duo should be used as a starting dose. Dose adjustments may be performed in increments of about 2.5 mcg to 5 mcg Viridal Duo. Most of the patients require between 10 and 20 mcg per injection. Some patients may need to be titrated to higher doses. Doses exceeding 20 mcg should be prescribed with particular care in patients with cardiovascular risk factors. The dose per injection should never exceed 40 mcg.

Dosage for self-injection therapy at home

Before starting treatment at home, each patient or the patient's partner has to be taught by a physician how to prepare the drug and perform the injection. In no cases should the injection therapy be started without precise instructions by the physician. The patient should only use his optimum individual dosage which has been pre-determined by his physician using the above-mentioned procedure. This dose should allow the patient to have an erection at home which should not last longer than one hour. If he experiences prolonged erections beyond 2 hours but less than 4 hours, the patient is recommended to contact his physician to re-establish the dose of the drug. Maximum injection frequency recommended is 2 or 3 times a week with an interval of at least 24 hours between the injections.

Follow-up

After the first injections and at regular intervals, e.g. every three months, the physician should re-evaluate the patient. Any local adverse reaction, e.g. haematoma, fibrosis or nodules should be noted and controlled. Following discussion with the patient, an adjustment of dosage may be necessary.

4.3 Contraindications

Hypersensitivity to the active substances or to any other ingredients.

Patients with diseases causing priapism e.g. sickle-cell disease, leukaemia and multiple myeloma or patients with anatomical deformation of the penis as cavernosal fibrosis or Peyronie's disease. Patients with penis implants should not use Viridal Duo.

Viridal Duo should not be used in men for whom sexual activity is contraindicated.

4.4 Special Warnings And Precautions For Use

The physician should carefully select patients suitable for self-injection therapy.

Sexual stimulation and intercourse can lead to cardiac and/or pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease.

Viridal Duo should be used with care in these patient groups and patients should be examined and cleared for stress resistance by a cardiologist before treatment.

Viridal Duo should be used with care in patients who have experienced transient ischaemic attacks.

Patients who experience a prolonged erection lasting longer than four hours should contact their physician immediately. Therefore it is recommended that the patient has an emergency telephone number of his attending physician or of a clinic experienced in therapy of erectile dysfunction. Prolonged erection may damage penile erectile tissue and lead to irreversible erectile dysfunction.

A benefit-risk evaulation is neccesary before using Viridal Duo in patients with pre-existing scarring, e.g. nodules of the cavernous body or pre-existing penile deviation or Peyronie's disease or clinically relevant phimosis, e.g. phimosis with risk of paraphimosis these patients should be treated with particular care, e.g. more frequent re-evaluation of the patient's condition.

Patients who have to be treated with alpha-adrenergic drugs due to prolonged erections (see: overdose) may in the case of concomitant therapy with monoamino-oxidase-inhibitors, develop a hypertensive crisis.

Other intracavernous drugs e.g. smooth muscle relaxing agents or alpha-adrenergic blocking agents may lead to prolonged erection and must not be used concomitantly.

The effects of a combination therapy of alprostadil with oral, intraurethral or topical medicinal products for erectile dysfunction are currently unknown.

Patients with blood clotting disorders or patients on therapy influencing blood clotting parameters should be carefully selected for treatment by the treating physician and treated with special care, e.g. monitoring of the clotting parameters, patients should be thoroughly educated by the prescriber about the associated risks and advised to exercise sufficient manual pressure on the injection site. This is because of the increased risk of bleeding.

To prevent abuse, self-injection therapy with Viridal Duo should not be used by patients with drug addiction and/or disturbances of psychological or intellectual development.

In cases of excessive use, e.g. higher frequencies than recommended, an increased risk of penile scarring cannot be excluded.

Use of intracavernous alprostadil offers no protection from the transmission of sexually transmitted diseases. Individuals who use alprostadil should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). In some patients, injection of Viridal Duo can induce a small amount of bleeding at the injection site. In patients infected with blood borne diseases, this could increase the transmission of such diseases to the partner. For this reason we recommend that a condom is used for intercourse after injecting Viridal Duo.

Viridal Duo is for intracavernous injection. Subcutaneous injection or injections at areas of the penis other than the cavernous body should be avoided.

The injection should be performed under hygienic conditions to avoid infections. In any condition that precludes safe self-injection like poor manual dexterity, poor visual acuity or morbid obesity, the partner should be trained in the injection technique and should perform the injection.

Up to now, there is no clinical experience in patients under 18 and over 75 years of age.

Viridal Duo does not interfere with ejaculation and fertility.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of smooth muscle relaxing drugs like papaverine or other drugs inducing erection like alpha-adrenergic blocking agents may lead to prolonged erection and should not be used in parallel with Viridal Duo.

Risks exist when using alpha-adrenergic drugs to terminate prolonged erections in patients with cardiovascular disorders or receiving MAO inhibitors.

The effects of blood pressure lowering and vasodilating drugs may be increased.

4.6 Pregnancy And Lactation

The natural amount of PGE1 present in the sperm may be increased by the PGE1 present in Viridal Duo. In case the partner is pregnant, a condom should be used in order to avoid irritation of the vagina and a risk for the foetus.

4.7 Effects On Ability To Drive And Use Machines

Viridal Duo may rarely induce a transient drop of blood pressure with subsequent impairment of reactivity that could interfere with patient's ability to drive or operate machinery.

4.8 Undesirable Effects

Undesirable effects frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000).

During administration of Viridal Duo the following undesirable effects may be observed:

General disorders and administration site condition

Common: burning sensation during injection and after the injection, sensation of tension in the penis and pain of mostly mild intensity at the site of injection.

Uncommon: spotlike haemorrhage/ spotlike bruises at the site of puncture, haemosiderin deposits, reddening and swellings at the site of injection, swellings of the preputium or the glans, and headache.

Reproductive system and breast disorders

Common: fibrotic alterations (e.g. fibrotic nodules, plaques at the site of injection or in the corpus cavernosum) can occur during long-term treatment.

Uncommon: fibrotic alterations associated with slight penile axis deviations. Prolonged erections of more than 4 hours' duration are uncommon (mainly seen during dose titration).

Rare: fibrotic changes of the cavernous body during a long term treatment lasting up to 4 years.

Cardiac disorders

Rare: circulatory effects such as short periods of hypotension and/or vertigo or dizziness.

Immune system disorders

Rare: allergic reactions ranging from cutaneous hypersensitivity such as rash, erythema, urticaria to anaphylactic/anaphylactoid reactions.

4.9 Overdose

Symptoms

Full rigid erections lasting more than four hours.

If the patient experiences a prolonged erection, he is advised to contact his attending physician or a urologic clinic nearby immediately.

Treatment strategy

Treatment of prolonged erection should be done by a physician experienced in the field of erectile dysfunction. If prolonged erection occurs, the following is recommended:

If the erection has lasted less than six hours:

− observation of the erection because spontaneous flaccidity frequently occurs.

If the erection has lasted longer than six hours:

− cavernous body injection of alpha-adrenergic substances (e.g. phenylephrine or epinephrine (adrenaline)). Risks exist when using drugs in patients with cardiovascular disorders or receiving MAO inhibitors. All patients should be monitored for cardiovascular effects when these drugs are used to terminate prolonged erections.

or

− aspiration of blood from the cavernous body.

Accidental systemic injection of high doses

Single dose rising tolerance studies in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Starting with a 40 mcg bolus intravenous dose, the frequency of drug-related adverse events increased in a dose-dependent manner, characterised mainly by facial flushing.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: Other urologicals G04BX 05

Alprostadil [Prostaglandin E₁ (PGE₁)], the active ingredient of Viridal Duo, is an endogenous compound derived from the essential fatty acid dihomogammalinolenic acid. Alprostadil is a potent smooth muscle relaxant that produces vasodilation and occurs in high concentrations in the human seminal fluid. Pre-contracted isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery were relaxed by alprostadil, while other prostanoids were less effective. Alprostadil has been shown to bind to specific receptors in the cavernous tissue of human and non-human primates.

The binding of alprostadil to its receptors is accompanied by an increase in intracellular cAMP levels. Human cavernosal smooth muscle cells respond to alprostadil by releasing intracellular calcium. Since relaxation of smooth muscle is associated with a reduction of the cytoplasmic free calcium concentration, this effect may contribute to the relaxing activity of this prostanoid.

Intracavernous injection of alprostadil in healthy monkeys resulted in penile elongation and tumescence without rigidity. The cavernous arterial blood flow was increased for a mean duration of 20 min. In contrast, intracavernous application of alprostadil to rabbits and dogs caused no erectile response.

Systemic intravascular administration of alprostadil leads to a vasodilation and reduction of systemic peripheral vascular resistance. A decrease in blood pressure can be observed after administration of high doses. Alprostadil has also been shown in animal and in vitro tests to reduce platelet reactivity and neutrophil activation. Additional alprostadil activity has been reported: increase in fibrinolytic activity of fibroblasts, improvement of erythrocyte deformability and inhibition of erythrocyte aggregation; inhibition of the proliferative and mitotic activity of non-striated myocytes; inhibition of cholesterol synthesis and LDL-receptor activity; and an increase in the supply of oxygen and glucose to ischaemic tissue along with improved tissue utilisation of these substrates.

5.2 Pharmacokinetic Properties

After reconstitution, alprostadil (PGE₁) dissociates from the α-cyclodextrin clathrate, and the two components have independent fates.

In symptomatic volunteers, systemic mean endogenous PGE₁ venous plasma concentrations measured before intracavernous injection are approximately 1 pg/ml. After injection of 20 mcg of alprostadil, the PGE₁ venous plasma concentrations increase rapidly to concentrations of about 10-20 pg/ml. The PGE₁ plasma concentrations return to concentrations close to the baseline within a few minutes. Approximately 90% of PGE₁ found in plasma is protein-bound.

Metabolism

Enzymatic oxidation of the C15-hydroxy group and reduction of the C13,14 double bond produce the primary metabolites, 15-keto-PGE₁, PGE_o (13,14-dihydro-PGE₁) and 15-keto-PGE_o. Only PGE_o and 15-keto-PGE_o have been detected in human plasma. Unlike the 15-keto metabolites, which are less pharmacologically active than the parent compound, PGE_o has a potency similar to that of PGE₁ in most respects.

In symptomatic volunteers, the mean endogenous PGE_o venous plasma concentrations measured before an intracavernous injection are approximately 1 pg/ml. After the injection of 20 mcg of alprostadil, the PGE_o plasma concentrations increase to concentrations of about 5 pg/ml.

Excretion

After further degradation of the primary metabolites by beta and omega oxidation, the resulting, more polar metabolites are excreted primarily with the urine (88%) and the faeces (12%) and there is no evidence of tissue retention of PGE₁ or its metabolites.

5.3 Preclinical Safety Data

Studies on local tolerance following single and repeated intracavernous injections of alprostadil or alprostadil alfadex in rabbits and/or monkeys, in monkeys up to 6 months with daily injection revealed in general good local tolerance. Possible adverse effects like haematomas and inflammations are more likely related to the injection procedure.

Within the 6 months study in male monkeys, there were no adverse effects of alprostadil alfadex on male reproductive organs.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance in male and female rats treated with 40-200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose on a body weight basis (MHRD < 1 mcg/kg).

Alprostadil was not fetotoxic or teratogenic at doses up to 5000 mcg/kg/day (7500 times the MHRD) in rats, 200 mcg/kg/day (300 times the MHRD) in rabbits and doses up to 20 mcg/kg/day (30 times the MHRD) in guinea pigs or monkeys.

Mutagenicity studies with alprostadil alfadex revealed no risk of mutagenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder for injection:

Lactose monohydrate

Alfadex

Diluent:

Sodium chloride

Water for injection.

6.2 Incompatibilities

It is not intended that this medicinal product be mixed with other medicinal products. Therefore in the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Shelf life for the product as packaged for sale: 4 years.

Shelf life after reconstitution: for immediate use only.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Administration devices:

1 reusable injector (starter kit)

1 double-chamber cartridge with dry substance and 1 ml 0.9% sterile sodium chloride solution.

1 injection needle 29G x ½ (0.33 mm x 12.7 mm)

1 alcohol swab to be obtained for each injection.

1. Cartons containing one colourless glass double-chamber cartridge, one injection needle 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

2. Cartons containing two colourless glass double-chamber cartridges, two injection needles 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

3. Cartons containing one, two or six colourless glass double-chamber cartridges and corresponding number of injection needles 29 G x ½ (0.33 mm x 12.7 mm) without reusable injector.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Fix the injection needle onto the front part of the injector.

Disinfect the tip of the cartridge with one of the alcohol swabs. Insert the cartridge into the reusable injector and fix it by screwing the thread part. Dissolve the drug substance in the front chamber of the cartridge by completely screwing the thread-part into the injector thus moving both rubber stoppers to the top of the cartridge and allowing the solvent in to the bottom chamber to reach the dry substance via the bypass of the cartridge. Shake slightly until a clear solution is produced.

Expel the air and adjust the prescribed dosage precisely prior to intracavernous injection.

After preparation of the solution, the injection must be performed using aseptic procedures into either the left or right cavernous body of the penile shaft. Care should be taken not to inject into penile vessels or nerves on the upper side of the penis and into the urethra on the under side. The injection should be completed within 5 to 10 seconds and manual pressure should be applied to the injection site for 2 to 3 minutes.

Unused solution must be discarded immediately.

Advice

The content of the front chamber of the cartridge consists of a white, dry powder, which forms a compact layer, approximately 8 mm in height. The layer may show cracks and crumble slightly.

In case of damage to the cartridge, the usually dry content of the front chamber becomes moist and sticky and extensively loses volume. Viridal Duo must not be used in this case.

The bottom chamber contains the clear, colourless sodium chloride solvent solution.

The dry substance dissolves immediately after addition of the sodium chloride solution. Initially after reconstitution the solution may appear slightly opaque due to the presence of bubbles. This is of no relevance and disappears within a short time to give a clear solution.

Disposal of needle: disable needle then dispose of in a sharps container.

Disposal of cartridge: no special requirements.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/0753

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd September 2010

10. Date Of Revision Of The Text

Metastron

Strontium-89 Chloride

Dosage Form: Injection

Rx ONLY

Metastron Description

Metastron is a sterile, non-pyrogenic, aqueus solution of Strontium-89 Chloride for intravenous administration. The solution contains no preservative.

Each milliliter contains:

    Strontium Chloride    10.9 - 22.6 mg

    Water for Injection    q.s. to 1 mL

The radioactive concentration is 37 MBq/mL, 1 mCi/mL, and the specific activity is 2.96-6.17 MBq/mg, 80-167 µCi/mg at calibration. The pH of the solution is 4 - 7.5.

PHYSICAL CHARACTERISTICS

Strontium-89 decays by beta emission with a physical half-life of 50.5 days. The maximum beta energy is 1.463 MeV (100%). The maximum range of β- from Strontium-89 in tissue is approximately 8 mm.

Radioactive decay factors to be applied to the stated value for radioactive concentration at calibration, when calculating injection volumes at the time of administration, are given in Table 1.

Table 1: Decay of Strontium-89

Day*	Factor	Day*	Factor
* Days before (-) or after (+) the calibration date stated on the vial.
-24	1.39	+6	0.92
-22	1.35	+8	0.90
-20	1.32	+10	0.87
-18	1.28	+12	0.85
-16	1.25	+14	0.83
-14	1.21	+16	0.80
-12	1.18	+18	0.78
-10	1.15	+20	0.76
-8	1.12	+22	0.74
-6	1.09	+24	0.72
-4	1.06	+26	0.70
-2	1.03	+28	0.68
0=calibration	1.00

Metastron - Clinical Pharmacology

Following intravenous injection, soluble strontium compounds behave like their calcium analogs, clearing rapidly from the blood and selectively localizing in bone mineral. Uptake of strontium by bone occurs preferentially in sites of active osteogenesis; thus primary bone tumors and areas of metastatic involvement (blastic lesions) can accumulate significantly greater concentrations of strontium than surrounding normal bone.

Strontium-89 Chloride is retained in metastatic bone lesions much longer than in normal bone, where turnover is about 14 days. In patients with extensive skeletal metastases, well over half of the injected dose is retained in the bones.

Excretion pathways are two-thirds urinary and one-third fecal in patients with bone metastases. Urinary excretion is higher in people without bone lesions. Urinary excretion is greatest in the first two days following injection.

Strontium-89 is a pure beta emitter and Strontium-89 Chloride selectively irradiates sites of primary and metastatic bone involvement with minimal irradiation of soft tissues distant from the bone lesions. (The maximum range in tissue is 8 mm; maximum energy is 1.463 MeV.) Mean absorbed radiation doses are listed under the Radiation Dosimetry section.

Clinical trials have examined relief of pain in cancer patients who have received therapy for bone metastases (external radiation to indexed sites) but in whom persistent pain recurred. In a multi-center Canadian placebo-controlled trial of 126 patients, pain relief occurred in more patients treated with a single injection of Metastron than in patients treated with an injection of placebo. Results are given in the following tables.

Table 2 compares the percentage and number of patients treated with Metastron or placebo who had reduced pain and no increase in analgesic or radiotherapy re-treatment.

Table 2: Comparison of the effects of Strontium-89 and placebo, as adjunct to radiotherapy, on treatment outcome over time.

Months Post-Treatment
	1	2	3	4	5	6
Metastron	71.4%	78.9%	60.6%	59.3%	36.4%	63.6%
	(n=42)	(n=38)	(n=33)	(n=27)	(n=22)	(n=22)
Placebo	61.4%	57.1%	55.9%	25.0%	31.8%	35.0%
	(n=44)	(n=35)	(n=34)	(n=24)	(n=22)	(n=20)

At each visit, treatment success, defined as a reduction in a patient's pain score without any increase in analgesic intake and without any supplementary radiotherapy at the index site, was more frequent among patients assigned to Metastron than to placebo.

Table 3 compares the number and percentage of patients treated with Metastron or placebo as an adjunct to radiotherapy who were pain free without analgesic at the intervals shown.

Table 3: Comparison of the effects of Strontium-89 and placebo, as adjunct to radiotherapy, on reduction of pain score and analgesic score to zero.

Months Post-Treatment
	1	2	3	4	5	6	9
Metastron	6	5	5	3	4	4	2
	14.3%	13.2%	15.2%	11.1%	18.2%	18.2%	18.2%
	(n=42)	(n=38)	(n=33)	(n=27)	(n=22)	(n=22)	(n=11)
Placebo	3	3	2	0	1	1	0
	6.8%	8.6%	5.9%		4.5%	5%
	(n=44)	(n=35)	(n=34)	(n=24)	(n=22)	(n=20)	(n=17)

The number of patients classified at each visit as treatment successes who were pain free at the index site and required no analgesics was consistently higher in the Metastron group.

New pain sites were less frequent in patients treated with Metastron.

In another clinical trial, pain relief was greater in a group of patients treated with Metastron compared with a group treated with non-radioactive strontium-88.

Indications and Usage for Metastron

Metastron (Strontium-89 Chloride Injection) is indicated for the relief of bone pain in patients with painful skeletal metastases.

The presence of bone metastases should be confirmed prior to therapy.

Contraindications

None known.

Warnings

Use of Metastron in patients with evidence of seriously compromised bone marrow from previous therapy or disease infiltration is not recommended unless the potential benefit of the treatment outweighs its risks. Bone marrow toxicity is to be expected following the administration of Metastron, particularly white blood cells and platelets. The extent of toxicity is variable. It is recommended that the patient's peripheral blood cell counts be monitored at least once every other week. Typically, platelets will be depressed by about 30% compared to pre-administration levels. The nadir of platelet depression in most patients is found between 12 and 16 weeks following administration of Metastron. White blood cells are usually depressed to a varying extent compared to pre-administration levels. Thereafter, recovery occurs slowly, typically reaching pre-administration levels six months after treatment unless the patient's disease or additional therapy intervenes.

In considering repeat administration of Metastron, the patient's hematologic response to the initial dose, current platelet level and other evidence of marrow depletion should be carefully evaluated.

Verification of dose and patient identification is necessary prior to administration because Metastron delivers a relatively high dose of radioactivity.

Metastron may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions

Metastron is not indicated for use in patients with cancer not involving bone. Metastron should be used with caution in patients with platelet counts below 60,000 and white cell counts below 2,400.

Radiopharmaceuticals should only be used by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Metastron, like other radioactive drugs, must be handled with care and appropriate safety measures taken to minimize radiation to clinical personnel.

In view of the delayed onset of pain relief, typically 7 to 20 days post injection, administration of Metastron to patients with very short life expectancy is not recommended.

A calcium-like flushing sensation has been observed in patients following a rapid (less than 30 second injection) administration.

Special precautions, such as urinary catheterization, should be taken following administration to patients who are incontinent to minimize the risk of radioactive contamination of clothing, bed linen and the patient's environment.

Metastron is excreted primarily by the kidneys. In patients with renal dysfunction, the possible risks of administering Metastron should be weighed against the possible benefits.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Data from a repetitive dose animal study suggests that Strontium-89 Chloride is a potential carcinogen. Thirty-three of 40 rats injected with Strontium-89 Chloride in ten consecutive monthly doses of either 250 or 350 µCi/kg developed malignant bone tumors after a latency period of approximately 9 months. No neoplasia was observed in the control animals. Treatment with Strontium-89 Chloride should be restricted to patients with well documented metastatic bone disease.

Adequate studies with Strontium-89 Chloride have not been performed to evaluate mutagenic potential or effects on fertility.

Pregnancy

Teratogenic effects

Pregnancy Category D. See Warnings section.

Nursing Mothers

Because Strontium acts as a calcium analog, secretion of Strontium-89 Chloride into human milk is likely. It is recommended that nursing be discontinued by mothers about to receive intravenous Strontium-89 Chloride. It is not known whether this drug is excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Adverse Reactions

A single case of fatal septicemia following leukopenia was reported during clinical trials. Most severe reactions of marrow toxicity can be managed by conventional means.

A small number of patients have reported a transient increase in bone pain at 36 to 72 hours after injection. This is usually mild and self-limiting, and controllable with analgesics. A single patient reported chills and fever 12 hours after injection without long-term sequelae.

Metastron Dosage and Administration

The recommended dose of Metastron is 148 MBq, 4 mCi, administered by slow intravenous injection (1-2 minutes).

Alternatively, a dose of 1.5 - 2.2 MBq/kg, 40-60 µCi/kg body weight may be used.

Repeated administrations of Metastron should be based on an individual patient's response to therapy, current symptoms, and hematologic status, and are generally not recommended at intervals of less than 90 days.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

RADIATION DOSIMETRY

The estimated radiation dose that would be delivered over time by the intravenous injection of 37 MBq, 1 mCi of Strontium-89 to a normal healthy adult is given in Table 4. Data are taken from the ICRP publication "Radiation Dose to Patients from Radiopharmaceuticals"-ICRP #53, Vol. 18, No. 1-4, Page 171, Pergamon Press, 1988.

Table 4: Strontium-89 Dosimetry

Organ	mGy/MBq	rad/mCi
Bone Surface	17.0	63.0
Red Bone Marrow	11.0	40.7
Lower Bowel Wall	4.7	17.4
Bladder Wall	1.3	4.8
Testes	0.8	2.9
Ovaries	0.8	2.9
Uterine Wall	0.8	2.9
Kidneys	0.8	2.9

When blastic osseous metastases are present, significantly enhanced localization of the radiopharmaceutical will occur with correspondingly higher doses to the metastases compared with normal bones and other organs.

The radiation dose hazard in handling Strontium-89 Chloride injection during dose dispensing and administration is similar to that from phosphorus-32. The beta emission has a range in water of about 8 mm (max.) and in glass of about 3 mm, but the bremsstrahlung radiation may augment the contact dose.

Measured values of the dose on the surface of the unshielded vial are about 65 mR/minute/mCi.

It is recommended that the vial be kept inside its transportation shield whenever possible.

How is Metastron Supplied

Metastron is supplied in a 10 mL vial containing 148 MBq, 4 mCi. The vial is shipped in a transportation shield with approximately 3 mm lead wall thickness, package insert, and two therapeutic agent warning labels.

The vial and its contents should be stored inside its transportation container at room temperature (15-25°C, 59-77°F).

The calibration date (for radioactivity content) and expiration date are quoted on the vial label. The expiration date will be 28 days after calibration. Stability studies have shown no change in any of the product characteristics monitored during routine product quality control over the period from manufacture to expiration.

This radiopharmaceutical is licensed by the Illinois Emergency Management Agency for distribution to persons licensed pursuant to 32 Illinois Adm. Code 330.260 (a) and Part 335 Subpart F.335.5010 or under equivalent licenses of the USNRC or an Agreement State.

NDC17156-524-01

Manufactured by:

GE Healthcare Ltd.

Amersham England

GE Healthcare

Medi-Physics, Inc.,

3350 North Ridge Avenue

Arlington Heights, IL 60004

Metastron is a trademark of GE Healthcare.

GE and the GE Monogram are trademarks of General Electric Company.

43-9000D

Revised February 2006

Metastron  strontium chloride, sr-89  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 17156-524 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Strontium Chloride, SR-89 (Strontium Chloride, SR-89) Active 1 MILLICURIE  In 1 MILLILITER Water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17156-524-01 5 VIAL In 1 BOX contains a VIAL 1 10 mL (MILLILITER) In 1 VIAL This package is contained within the BOX (17156-524-01)

Revised: 08/2007GE Healthcare, Medi-Physics, Inc.

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