Aldurazyme 100 U / ml concentrate for solution for infusion

1. Name Of The Medicinal Product

Aldurazyme 100 U/ml concentrate for solution for infusion

2. Qualitative And Quantitative Composition

1 ml contains 100 U (approximately 0.58 mg) of laronidase.

Each vial of 5 ml contains 500 U of laronidase.

The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute.

Laronidase is a recombinant form of human α-L-iduronidase and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Excipients

Each vial of 5 ml contains 1.29 mmol sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

A clear to slightly opalescent, and colourless to pale yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-neurological manifestations of the disease (see section 5.1).

4.2 Posology And Method Of Administration

Posology

The recommended dosage regimen of Aldurazyme is 100 U/kg body weight administered once every week as an intravenous infusion. The initial infusion rate of 2 U/kg/h may be incrementally increased every fifteen minutes, if tolerated, to a maximum of 43 U/kg/h. The total volume of the administration should be delivered in approximately 3-4 hours. For information on pre-treatment, see section 4.4.

Paediatric population

No dose adjustment is necessary for the paediatric population.

The safety and efficacy of Aldurazyme in patients older than 65 years have not been established and no dosage regimen can be recommended in these patients.

The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not been evaluated and no dosage regimen can be recommended in these patients.

Method of administration

Aldurazyme treatment should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases. Administration of Aldurazyme should be carried out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.

For instruction on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Severe hypersensitivity (e.g. anaphylactic reaction) to the active substance or to any of the excipients (see sections 4.4 and 4.8).

4.4 Special Warnings And Precautions For Use

Patients treated with Aldurazyme may develop infusion-associated reactions (IARs), defined as any related adverse event occurring during the infusion or until the end of the infusion day (see section 4.8). Some of these IARs may be severe (see below).

Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associated reactions, delayed reactions and possible immunological reactions reported. Antibody status should be regularly monitored and reported.

Severe infusion associated reactions have been reported in patients with pre-existent severe underlying upper airway involvement and therefore specifically these patients should continue to be closely monitored and only be infused with Aldurazyme in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.

Patients with an acute underlying illness at the time of Aldurazyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration of Aldurazyme.

Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment.

Patients who have developed antibodies or symptoms of IARs should be treated with caution when administering Aldurazyme (see sections 4.3 and 4.8).

In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling the patient to continue treatment.

As there is little experience on resumption of treatment following prolonged interruption, use caution due to the theoretical increased risk of hypersensitivity reaction after treatment interruption.

With initial administration of Aldurazyme or upon re-administration following interruption of treatment, it is recommended that patients be administered pretreatment medicines(antihistamines and/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs. If clinically indicated, administration of pretreatment medications with subsequent infusions of Aldurazyme should be considered.

In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ibuprofen should be considered and/or a reduction in the infusion rate to half the infusion rate at which the reaction occurred.

In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and treatment with antihistamines and paracetamol/ibuprofen should be considered. The infusion can be restarted with a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the reaction occurred.

In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pretreatment should be considered (antihistamines and paracetamol/ibuprofen and/or corticosteroids) and a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the previous reaction occurred.

As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible.

If these reactions occur, immediate discontinuation of Aldurazyme is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed.

This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution (see section 6.6). To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed. Based on its metabolism, laronidase is an unlikely candidate for Cytochrome P450 mediated interactions.

Aldurazyme should not be administered simultaneously with chloroquine or procaine due to a potential risk of interference with the intracellular uptake of laronidase.

4.6 Pregnancy And Lactation

There are inadequate data on the use of Aldurazyme in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Therefore Aldurazyme should not be used during pregnancy unless clearly necessary.

Laronidase may be excreted in milk. Because there are no data available in neonates exposed to laronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment). Some of the IARs were severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased, tachycardia and chills.

ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: very common (

MedDRA System Organ Class	MedDRA Preferred Term	Frequency
Investigations	Body temperature increased, oxygen saturation decreased	Common
Cardiac disorders	Tachycardia	Common
Nervous system disorders	Headache	Very common
Paraesthesia, dizziness	Common
Respiratory, thoracic and mediastinal disorders	Respiratory distress, dyspnoea, cough	Common
Gastrointestinal disorders	Nausea, abdominal pain	Very common
Vomiting, diarrhoea	Common
Skin and subcutaneous tissue disorders	Rash	Very common
Angioneurotic edema, swelling face, urticaria, pruritus, cold sweat, alopecia, hyperhidrosis	Common
Musculoskeletal and connective tissue disorders	Arthropathy, arthralgia, back pain, pain in extremity	Very common
Musculoskeletal pain	Common
Vascular disorders	Flushing	Very common
Hypotension, pallor, peripheral coldness	Common
General disorders and administration site conditions	Pyrexia, infusion site reaction	Very common
Chills, feeling hot, feeling cold, fatigue, influenza like illness	Common
Immune system disorders	Anaphylactic reaction	Common
Psychiatric disorders	Restlessness	Common

A single patient with pre-existing airway compromise developed a severe reaction three hours from the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction, requiring tracheostomy. This patient tested positive for IgE.

Post-marketing experience of infusion associated reactions revealed reporting of pyrexia, chills, vomiting, tachypnoea, erythema and cyanosis, in which some of these reactions were severe. Additionally, a few patients who had a prior history of severe MPS I- related upper airway and pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and facial oedema (see section 4.4).

There have been reports of extravasation in patients treated with Aldurazyme.

Paediatric population

ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to moderate in severity.

MedDRA System Organ Class	MedDRA Preferred term	Frequency
Investigations	blood pressure increased	Very common
oxygen saturation decreased	Very common
Cardiac disorders	tachycardia	Very common
General disorders and administration site conditions	pyrexia	Very common
chills	Very common

In a phase 4 study 33 MPS1 patients received 1 of 4 dose regimens: 100 U/Kg IV every week (recommended dose), 200 U/Kg IV every week, 200 U/Kg IV every 2 weeks or 300 U/Kg IV every 2 weeks. The recommended dose group had the fewest number of patients who experienced ADRs and IARs. The type of IARs was similar to those seen in other clinical studies.

Immunogenicity

Almost all patients developed IgG antibodies to laronidase. Most patients seroconverted within 3 months of initiation of treatment; although seroconversion in patients under 5 years old with a more severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years and older). By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titers showed variable reduction in urinary GAG. The clinical significance of this finding is unknown since there were no consistent relationships between IgG antibody level and clinical efficacy endpoints.

In addition 60 patients in the Phase 2 and 3 studies were tested for in-vitro neutralising effects. Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or urinary GAG reduction.

The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies. The occurrence of IgE antibodies was not fully explored.

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Enzymes,

ATC code: A16AB05.

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan sulfate and heparan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors.

Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kD. Laronidase is comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modifications sites.

Three clinical trials were performed with Aldurazyme to assess its efficacy and safety. One clinical study focussed mainly on assessing the effect of Aldurazyme on the systemic manifestations of MPS I such as poor endurance, restrictive lung disease, upper airway obstruction, reduced joint range of motion, hepatomegaly and visual impairment. One study mainly assessed the safety and pharmacokinetics of Aldurazyme in patients less than 5 years old, but some efficacy measurements were included as well. The third study was conducted to evaluate the pharmacodynamics and safety of different dose regimens of Aldurazyme.

To date there are no clinical data that demonstrate any benefit on the neurological manifestations of the disorder.

The safety and efficacy of Aldurazyme was assessed in a randomised, double-blind, placebo controlled, Phase 3 Study of 45 patients, ranging in age from 6 to 43 years. Although patients representing the full range of the disease spectrum were enrolled, the majority of the patients were of the intermediate phenotype, with only one patient exhibiting the severe phenotype. Patients were enrolled with a Forced Vital Capacity (FVC) less than 80% of the predicted value and had to be able to stand for 6 minutes and to walk 5 meters. Patients received either 100 U/kg of Aldurazyme or placebo every week for a total of 26 weeks. The primary efficacy endpoints were changes in percent of predicted normal FVC and absolute distance travelled in the six-minute walk test (6MWT). All patients subsequently enrolled in an open label extension study where they all received 100 U/kg of Aldurazyme every week for an additional 3.5 years (182 weeks).

Following 26 weeks of therapy, Aldurazyme-treated patients showed improved respiratory function and walking ability as compared to placebo as indicated below.

	Phase 3, 26 weeks of treatment compared to placebo
			p value	Confidence interval (95%)
Percent Predicted FVC (percentage point)	mean	5.6	-
median	3.0	0.009	0.9 - 8.6
6MWT (meters)	mean	38.1	-
median	38.5	0.066	-2.0 - 79.0

The open label extension study showed improvement and/or maintenance of these effects up to 208 weeks in the Aldurazyme/Aldurazyme group and 182 weeks in the Placebo/Aldurazyme group as indicated in the table below.

	Aldurazyme/Aldurazyme	Placebo/Aldurazyme
	At 208 weeks	At 182 weeks
Mean change from pre-treatment baseline
Percent predicted FVC (%)1	- 1.2	- 3.3
6 MWT (meters)	+ 39.2	+ 19.4
Apnea/Hypopnea Index (AHI)	- 4.0	- 4.8
Shoulder flexion Range Of Motion (degrees)	+ 13.1	+ 18.3
CHAQ/HAQ Disability Index 2	- 0.43	- 0.26

¹The decrease in percent predicted FVC is not clinically significant over this timeframe, and absolute lung volumes continued to increase commensurate with changes in height in growing paediatric patients.

² Both groups exceeded the minimal clinically important difference (-0.24)

Of the 26 patients with abnormal liver volumes at pre-treatment baseline, 22 (85%) achieved a normal liver size by the end of the study. There was a rapid reduction in the excretion of urinary GAG (µg/mg creatinine) within the first 4 weeks, which was maintained through the remainder of the study. Urinary GAG levels decreased by 77% and 66% in the Placebo/Aldurazyme and Aldurazyme/Aldurazyme groups, respectively; at the end of the study one-third of the patients (15 of 45) had reached normal urinary GAG levels.

To address the heterogeneity in disease manifestation across patients, using a composite endpoint that summed up clinically significant changes across five efficacy variables (percent predicted normal FVC, 6MWT distance, shoulder flexion range of motion, AHI, and visual acuity) the global response was an improvement in 26 patients (58%), no change in 10 patients (22%), and a deterioration in 9 patients (20%).

A Phase 2 open-label, 1-year study was conducted that mainly assessed the safety and pharmacokinetics of Aldurazyme in 20 patients less than 5 years of age at the time of enrolment (16 patients with the severe phenotype and 4 with the intermediate phenotype). The patients were scheduled to receive Aldurazyme 100 U/kg weekly infusions for a total duration of 52 weeks. Four patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary GAG levels at Week 22.

Eighteen patients completed the study. Aldurazyme was well tolerated at both dosages. The mean urinary GAG level declined by 50% at Week 13 and was reduced by 61% at the end of the study. Upon study completion, all patients showed reductions in liver size and 50% (9/18) had normal liver size. The proportion of patients with mild left ventricular hypertrophy decreased from 53% (10/19) to 17% (3/18), and mean left ventricular mass normalized for body surface area decreased by 0.9 Z-Score (n=17). Several patients showed an increase in height (n=7) and weight (n=3) for age Z-score. The younger patients with the severe phenotype (< 2.5 years) and all 4 patients with the intermediate phenotype exhibited a normal rate of mental development, whereas the older patients with a severe phenotype made limited or no gains in cognition.

A phase 4 study was conducted to evaluate the pharmacodynamic effects on urinary GAGs, liver volume, and 6MWT, of different Aldurazyme dose regimens. In this 26-week open label study, 33 MPS1 patients received 1 of 4 dose regimens of Aldurazyme: 100 U/Kg IV every week (recommended dose), 200 U/Kg IV every week, 200 U/Kg IV every 2 weeks; or 300 U/Kg IV every 2 weeks. No definite benefit was shown with the higher doses over the recommended dose. The 200 U/Kg IV every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions; however, there is no evidence that the long term clinical efficacy of these two dose regimens is equivalent.

This medicinal product has been authorised under “Exceptional Circumstances”.

This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

5.2 Pharmacokinetic Properties

After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of 100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26.

Parameter	Infusion 1 Mean ± SD	Infusion 12 Mean ± SD	Infusion 26 Mean ± SD
Cmax (U/ml)	0.197 ± 0.052	0.210 ± 0.079	0.302 ± 0.089
AUC (h•U/ml)	0.930 ± 0.214	0.913 ± 0.445	1.191 ± 0.451
CL (ml/min/kg)	1.96 ± 0.495	2.31 ± 1.13	1.68 ± 0.763
Vz (l/kg)	0.604 ± 0.172	0.307 ± 0.143	0.239 ± 0.128
Vss (l/kg)	0.440 ± 0.125	0.252 ± 0.079	0.217 ± 0.081
t1/2 (h)	3.61 ± 0.894	2.02 ± 1.26	1.94 ± 1.09

C_max showed an increase over time. The volume of distribution decreased with continued treatment, possibly related to antibody formation and/or decreased liver volume.

The pharmacokinetic profile in patients less than 5 years old was similar to that of older and less severely affected patients.

Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for clearance (see section 4.2).

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic and carcinogenic potential are not expected.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Polysorbate 80

Water for injections

6.2 Incompatibilities

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

6.3 Shelf Life

Unopened vials:

3 years

Diluted solutions:

From a microbiological safety point of view, the product should be used immediately. If not used immediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution has taken place under controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

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

6.5 Nature And Contents Of Container

5 ml concentrate for solution in a vial (type I glass) with a stopper (siliconised chlorobutyl rubber) and a seal (aluminium) with a flip-off cap (polypropylene).

Pack sizes: 1, 10 and 25 vials.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Each vial of Aldurazyme is intended for single use only. The concentrate for solution for infusion has to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is recommended that the diluted Aldurazyme solution be administered to patients using an infusion set equipped with a 0.2 µm in-line filter.

Preparation of the Aldurazyme Infusion (Use Aseptic Technique)

• Determine the number of vials to be diluted based on the individual patient's weight. Remove the required vials from the refrigerator approximately 20 minutes in advance in order to allow them to reach room temperature (below 30˚C).

• Before dilution, visually inspect each vial for particulate matter and discoloration. The clear to slightly opalescent and colourless to pale yellow solution should be free of visible particles. Do not use vials exhibiting particles or discoloration.

• Determine the total volume of infusion based on the individual patient's weight, either 100 ml (if body weight is less or equal than 20 kg) or 250 ml (if body weight is more than 20 kg) of sodium chloride 9 mg/ml (0.9%) solution for infusion.

• Withdraw and discard a volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion from the infusion bag equal to the total volume of Aldurazyme to be added.

• Withdraw the required volume from the Aldurazyme vials and combine the withdrawn volumes.

• Add the combined volumes of Aldurazyme to the sodium chloride 9 mg/ml (0.9%) solution for infusion.

• Mix the solution for infusion gently.

• Prior to use visually inspect the solution for particulate matter. Only clear and colourless solutions without visible particles should be used.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands.

8. Marketing Authorisation Number(S)

EU/1/03/253/001-003

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 10/06/2003

Date of latest renewal: 10/06/2008

10. Date Of Revision Of The Text

04/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/

Cordarone

Generic Name: amiodarone (Oral route)

a-mee-OH-da-rone

Oral route(Tablet)

Amiodarone has several potentially fatal toxicities, the most important of which is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis). Liver injury is common, but is usually mild and evidenced only by abnormal liver enzymes. Overt liver disease can occur, however, and has been fatal in a few cases. Amiodarone can exacerbate the arrhythmia, e.g., by making the arrhythmia less well tolerated or more difficult to reverse. Patients with the indicated arrhythmias must be hospitalized while the loading dose is given, and a response generally requires at least one week, usually two or more .

Commonly used brand name(s)

In the U.S.

• Cordarone


• Pacerone

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiarrhythmic, Group III

Chemical Class: Benzofuran

Uses For Cordarone

Amiodarone is used to treat life-threatening heart rhythm problems called ventricular arrhythmias. This medicine is used in patients who have already been treated with other medicines that did not work.

Amiodarone belongs to the group of medicines known as antiarrhythmics. It works directly on the heart tissue and will slow the nerve impulses in the heart. This helps keep the heart rhythm normal.

This medicine is available only with your doctor's prescription.

Before Using Cordarone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of amiodarone in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amiodarone in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving amiodarone.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bepridil


• Cisapride


• Dronedarone


• Grepafloxacin


• Indinavir


• Levomethadyl


• Mesoridazine


• Nelfinavir


• Pimozide


• Posaconazole


• Ritonavir


• Saquinavir


• Sparfloxacin


• Terfenadine


• Thioridazine


• Tipranavir


• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Acecainide


• Alprenolol


• Amiodarone


• Amisulpride


• Amitriptyline


• Amlodipine


• Amoxapine


• Amprenavir


• Apomorphine


• Aprindine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Atazanavir


• Atenolol


• Azimilide


• Azithromycin


• Betaxolol


• Bevantolol


• Bisoprolol


• Boceprevir


• Bretylium


• Bucindolol


• Carteolol


• Carvedilol


• Celiprolol


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clozapine


• Crizotinib


• Darunavir


• Dasatinib


• Delavirdine


• Desipramine


• Dibenzepin


• Digoxin


• Dilevalol


• Diltiazem


• Disopyramide


• Dofetilide


• Dolasetron


• Doxepin


• Droperidol


• Eletriptan


• Enflurane


• Erythromycin


• Esmolol


• Etravirine


• Felodipine


• Fentanyl


• Fingolimod


• Flecainide


• Fluconazole


• Flunarizine


• Fluoxetine


• Fosamprenavir


• Foscarnet


• Gallopamil


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Halothane


• Ibutilide


• Iloperidone


• Imipramine


• Iohexol


• Isoflurane


• Isradipine


• Itraconazole


• Ketoconazole


• Labetalol


• Lacidipine


• Lapatinib


• Lercanidipine


• Levobunolol


• Levofloxacin


• Lidocaine


• Lidoflazine


• Lopinavir


• Loratadine


• Lorcainide


• Lovastatin


• Lumefantrine


• Manidipine


• Mefloquine


• Mepindolol


• Methadone


• Metipranolol


• Metoprolol


• Metronidazole


• Mibefradil


• Moricizine


• Moxifloxacin


• Nadolol


• Nebivolol


• Nicardipine


• Nifedipine


• Nilotinib


• Nilvadipine


• Nimodipine


• Nisoldipine


• Nitrendipine


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Oxprenolol


• Paliperidone


• Pazopanib


• Penbutolol


• Pentamidine


• Perflutren Lipid Microsphere


• Perhexiline


• Pindolol


• Pranidipine


• Prilocaine


• Probucol


• Prochlorperazine


• Promethazine


• Propafenone


• Propranolol


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Rifampin


• Risperidone


• Salmeterol


• Sematilide


• Sertindole


• Simvastatin


• Sirolimus


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Spiramycin


• St John's Wort


• Sulfamethoxazole


• Sultopride


• Sunitinib


• Tacrolimus


• Talinolol


• Tedisamil


• Telaprevir


• Telithromycin


• Tertatolol


• Tetrabenazine


• Timolol


• Tizanidine


• Toremifene


• Trazodone


• Trifluoperazine


• Trimethoprim


• Trimipramine


• Vandetanib


• Vardenafil


• Vasopressin


• Vemurafenib


• Verapamil


• Voriconazole


• Warfarin


• Ziprasidone


• Zolmitriptan


• Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abarelix


• Acenocoumarol


• Aprindine


• Cholestyramine


• Clonazepam


• Clopidogrel


• Cyclosporine


• Dicumarol


• Digitoxin


• Flecainide


• Fosphenytoin


• Methotrexate


• Nevirapine


• Phenytoin


• Procainamide


• Rifapentine


• Rosuvastatin


• Theophylline


• Tolterodine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• AV block (type of abnormal heart rhythm), with no pacemaker or


• Bradycardia (slow heartbeat) or


• Cardiogenic shock or


• Sick sinus syndrome (type of abnormal heart rhythm), with no pacemaker—Should not be used in patients with these conditions.

• Eye or vision problems or


• Heart disease (e.g., congestive heart failure) or


• Heart rhythm problems (e.g., QT prolongation) or


• Hypokalemia (low potassium in the blood) or


• Hypomagnesemia (low magnesium in the blood) or


• Hypotension (low blood pressure) or


• Lung disease or other breathing problems (e.g., interstitial pneumonitis) or


• Thyroid problems—Use with caution. May make these conditions worse.

Proper Use of amiodarone

This section provides information on the proper use of a number of products that contain amiodarone. It may not be specific to Cordarone. Please read with care.

You will receive your first dose of this medicine in a hospital. Your doctor will watch you closely after you take this medicine to make sure you do not have any serious side effects.

Take amiodarone exactly as directed by your doctor even though you may feel well. Do not take more medicine than your doctor ordered and do not miss any doses. It may take one or two weeks before your body responds to this medicine.

This medicine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food, but take amiodarone the same way each time.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For ventricular arrhythmias:
    
    • Adults—At first, 800 to 1600 milligrams (mg) per day taken in divided doses. Your doctor may adjust your dose as needed and tolerated.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Cordarone

It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Tell your doctor right away if you are having shortness of breath, chest tightness, wheezing, or any type of breathing problem while using this medicine.

This medicine can cause changes in your heart rhythm, such as a condition called QT prolongation. It may cause fainting or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

Liver problems may occur while you are using this medicine. Stop using this medicine and check with your doctor right away if you are having more than one of these symptoms: abdominal pain or tenderness; clay-colored stools; dark urine; decreased appetite; fever; headache; itching; loss of appetite; nausea and vomiting; skin rash; swelling of the feet or lower legs; unusual tiredness or weakness; or yellow eyes or skin.

Check with your doctor immediately if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

You may need to carry a medical identification card or bracelet showing that you are taking this medicine. Ask your doctor about this.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. You may need to stop using this medicine several days before having surgery or medical tests.

Amiodarone increases the sensitivity of your skin to sunlight; too much sun exposure could cause a serious sunburn. Your skin may continue to be sensitive to sunlight for several months after treatment is stopped. Use a sunscreen when you are outdoors. Wear protective clothing and hats. Avoid sunlamps and tanning beds.

After you have taken this medicine for a long time, it may cause a blue-gray color to appear on your skin, especially in areas exposed to the sun, such as your face, neck, and arms. This color will usually fade after treatment with amiodarone has ended, although it may take several months. Check with your doctor if this color change occurs.

Grapefruits and grapefruit juice may increase the side effects from amiodarone by increasing the amount of this medicine in your body. You should not eat grapefruit or drink grapefruit juice while you are using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's wort) or vitamin supplements.

Cordarone Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Cough


• dizziness, lightheadedness, or fainting


• fever (slight)


• numbness or tingling in the fingers or toes


• painful breathing


• sensitivity of the skin to sunlight


• shortness of breath


• trembling or shaking of the hands


• trouble with walking


• unusual and uncontrolled movements of the body


• weakness of the arms or legs

Less common

• Blue-gray coloring of the skin on the face, neck, and arms


• blurred vision or blue-green halos seen around objects


• coldness


• dry eyes


• dry, puffy skin


• fast or irregular heartbeat


• nervousness


• pain and swelling in the scrotum


• sensitivity of the eyes to light


• sensitivity to heat


• slow heartbeat


• sweating


• swelling of the feet or lower legs


• trouble with sleeping


• unusual tiredness


• weight gain or loss

Rare

• Skin rash


• yellow eyes or skin

Incidence not known

• Abdominal or stomach pain


• agitation


• back, leg, or stomach pains


• bleeding gums


• blistering, peeling, or loosening of the skin


• bloating


• blood in the urine


• bloody, black, or tarry stools


• blue lips, fingernails, or skin


• blurred or double vision


• chest pain


• chills


• clay-colored stools


• coma


• confusion


• confusion as to time, place, or person


• coughing or spitting up blood


• cracks in the skin


• dark urine


• decreased urine output


• depression


• diarrhea


• difficult or labored breathing


• difficult urination


• dry cough


• eye pain


• fast heartbeat


• fatigue


• general body swelling


• high fever


• holding false beliefs that cannot be change by fact


• hostility


• inability to have or keep an erection


• indigestion


• irregular, fast or slow, or shallow breathing


• irritability


• itching


• joint or muscle pain


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• lethargy


• loss in sexual ability, desire, drive, or performance


• loss of heat from the body


• lower back or side pain


• mood or mental change


• muscle cramps or spasms


• muscle pain or stiffness


• muscle twitching


• no breathing


• noisy breathing


• nosebleeds


• pain in the abdomen, groin, or scrotum


• pain or burning with urination


• pains in the stomach, side, or abdomen, possibly radiating to the back


• pale skin


• pinpoint red spots on the skin


• rapid weight gain


• rash


• red skin lesions, often with a purple center


• red, irritated eyes


• red, swollen skin


• scaly skin


• seeing, hearing, or feeling things that are not there


• seizures


• severe headache


• sneezing


• sore throat


• sores, ulcers, or white spots on the lips or in mouth


• stupor


• swelling of the face, ankles, or hands


• swelling of the scrotum


• swollen or painful glands


• tightness in the chest


• troubled breathing


• unpleasant breath odor


• unusual bleeding or bruising


• unusual excitement, nervousness, or restlessness


• unusual tiredness or weakness


• vomiting of blood


• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Constipation


• headache


• loss of appetite


• nausea and vomiting

Less common

• Bitter or metallic taste


• decrease in sexual interest


• decreased sexual ability in males


• dizziness


• flushing of the face

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Cordarone side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Cordarone resources

• Cordarone Side Effects (in more detail)
• Cordarone Use in Pregnancy & Breastfeeding
• Drug Images
• Cordarone Drug Interactions
• Cordarone Support Group
• 2 Reviews for Cordarone - Add your own review/rating

• Cordarone Prescribing Information (FDA)


• Cordarone MedFacts Consumer Leaflet (Wolters Kluwer)


• Amiodarone Prescribing Information (FDA)


• Amiodarone Professional Patient Advice (Wolters Kluwer)


• Amiodarone Hydrochloride Monograph (AHFS DI)


• Nexterone Prescribing Information (FDA)


• Nexterone Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Nexterone Consumer Overview


• Pacerone Prescribing Information (FDA)

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• Arrhythmia
• Supraventricular Tachycardia
• Ventricular Fibrillation
• Ventricular Tachycardia

Pentacel

Dosage Form: injection
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Pentacel® is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis and invasive disease due to Haemophilus influenzae type b. Pentacel vaccine is approved for use as a four dose series in children 6 weeks through 4 years of age (prior to fifth birthday).

2. DOSAGE AND ADMINISTRATION

. Immunization Series

Pentacel vaccine is to be administered as a 4 dose series at 2, 4, 6 and 15-18 months of age. The first dose may be given as early as 6 weeks of age. Four doses of Pentacel vaccine constitute a primary immunization course against pertussis. Three doses of Pentacel vaccine constitute a primary immunization course against diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis; the fourth dose is a booster for diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis immunizations. [See 14 Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5).]

Mixed Sequences of Pentacel Vaccine and DTaP Vaccine

While Pentacel and DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [DTaP], Sanofi Pasteur Limited) vaccines contain the same pertussis antigens, manufactured by the same process, Pentacel vaccine contains twice the amount of detoxified pertussis toxin (PT) and four times the amount of filamentous hemagglutinin (FHA) as DAPTACEL vaccine. Pentacel vaccine may be used to complete the first 4 doses of the 5-dose DTaP series in infants and children who have received 1 or more doses of DAPTACEL vaccine and are also scheduled to receive the other antigens of Pentacel vaccine. Children who have completed a 4-dose series with Pentacel vaccine should receive a fifth dose of DTaP vaccine using DAPTACEL at 4-6 years of age. However, data are not available on the safety and immunogenicity of mixed sequences of Pentacel vaccine and DAPTACEL vaccine for successive doses of the DTaP series.

Data are not available on the safety and immunogenicity of using mixed sequences of Pentacel vaccine and DTaP vaccine from different manufacturers.

Mixed Sequences of Pentacel Vaccine and IPV Vaccine

Pentacel vaccine may be used in infants and children who have received 1 or more doses of another licensed IPV vaccine and are scheduled to receive the antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children.

The Advisory Committee on Immunization Practices (ACIP) recommends that the final dose in the 4-dose IPV series be administered at age ≥4 years. (1) When Pentacel vaccine is administered at ages 2, 4, 6, and 15-18 months, an additional booster dose of IPV vaccine should be administered at age 4-6 years, resulting in a 5-dose IPV series. (1)

Mixed Sequences of Pentacel Vaccine and Haemophilus b Conjugate Vaccine

Pentacel vaccine may be used to complete the vaccination series in infants and children previously vaccinated with one or more doses of Haemophilus b Conjugate Vaccine (either separately administered or as part of another combination vaccine), who are also scheduled to receive the other antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children. If different brands of Haemophilus b Conjugate Vaccines are administered to complete the series, three primary immunizing doses are needed, followed by a booster dose.

. Administration

Just before use, thoroughly but gently shake the vial of DTaP-IPV component, withdraw the entire liquid content and inject into the vial of the lyophilized ActHIB vaccine component. Shake the vial now containing Pentacel vaccine thoroughly until a cloudy, uniform, white to off-white (yellow tinge) suspension results. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If these conditions exist, Pentacel vaccine should not be administered.

Withdraw and administer a 0.5 mL dose of Pentacel vaccine intramuscularly. Pentacel vaccine should be used immediately after reconstitution. Refer to Figures 1, 2, 3, 4 and 5.

Pentacel Vaccine: Instructions For Reconstitution of ActHIB Vaccine Component With DTaP-IPV Component

In infants younger than 1 year, the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.

Do not administer this product intravenously or subcutaneously.

Pentacel vaccine should not be mixed in the same syringe with other parenteral products.

3. DOSAGE FORMS AND STRENGTHS

Pentacel vaccine is a suspension for injection (0.5-mL dose) supplied as a liquid vaccine component that is combined through reconstitution with a lyophilized vaccine component, both in single dose vials. [See Dosage and Administration (2.2) and How Supplied/Storage and Handling (16).]

4. CONTRAINDICATIONS

. Hypersensitivity

A severe allergic reaction (eg, anaphylaxis) after a previous dose of Pentacel vaccine or any other diphtheria toxoid, tetanus toxoid, or pertussis-containing vaccine, inactivated poliovirus vaccine or H influenzae type b vaccine, or any ingredient of this vaccine is a contraindication to administration of Pentacel vaccine. [See Description (11).]

. Encephalopathy

Encephalopathy (eg, coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis-containing vaccine, including Pentacel vaccine.

. Progressive Neurologic Disorder

Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing vaccine including Pentacel vaccine. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.

5. WARNINGS AND PRECAUTIONS

. Management of Acute Allergic Reactions

Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.

. Adverse Reactions Following Prior Pertussis Vaccination

If any of the following events occur within the specified period after administration of a pertussis vaccine, the decision to administer Pentacel vaccine should be based on careful consideration of potential benefits and possible risks.

• Temperature of ≥40.5°C (≥105°F) within 48 hours, not attributable to another identifiable cause.


• Collapse or shock-like state (hypotonic-hyporesponsive episode (HHE)) within 48 hours.


• Persistent, inconsolable crying lasting ≥3 hours within 48 hours.


• Seizures with or without fever within 3 days.

. Guillain-Barré Syndrome and Brachial Neuritis

A review by the Institute of Medicine (IOM) found evidence for a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome. (2) If Guillain-Barré syndrome occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the decision to give Pentacel vaccine or any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.

. Infants and Children with a History of Previous Seizures

For infants or children with a history of previous seizures, an appropriate antipyretic may be administered (in the dosage recommended in its prescribing information) at the time of vaccination with a vaccine containing acellular pertussis antigens (including Pentacel vaccine) and for the following 24 hours, to reduce the possibility of post-vaccination fever.

. Limitations of Vaccine Effectiveness

Vaccination with Pentacel vaccine may not protect all individuals.

. Altered Immunocompetence

If Pentacel vaccine is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained. [See Drug Interactions (7.2).]

6. ADVERSE REACTIONS

. Data from Clinical Studies

Rates of adverse reactions varied by dose number. The most frequent (>50% of participants) systemic reactions following any dose were fussiness/irritability and inconsolable crying. The most frequent (>30% of participants) injection site reactions following any dose were tenderness and increased circumference of the injected arm.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events.

The safety of Pentacel vaccine was evaluated in four clinical studies in which a total of 5,980 participants received at least one dose of Pentacel vaccine. In three of the studies, conducted in the US, a total of 4,198 participants were enrolled to receive four consecutive doses of Pentacel vaccine. In the fourth study, conducted in Canada, 1,782 participants previously vaccinated with three doses of Pentacel vaccine received a fourth dose. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in these studies are provided in Table 1.

Across the four studies, 50.8% of participants were female. Among participants in the three US studies, 64.5% were Caucasian, 9.2% were Black, 12.9% were Hispanic, 3.9% were Asian, and 9.5% were of other racial/ethnic groups. In the two controlled studies, the racial/ethnic distribution of participants who received Pentacel and Control vaccines was similar. In the Canadian fourth dose study, 86.0% of participants were Caucasian, 1.9% were Black, 0.8% were Hispanic, 4.3% were Asian, 2.0% were East Indian, 0.5% were Native Indian, and 4.5% were of other racial/ethnic groups.

Table 1: Clinical Safety Studies of Pentacel Vaccine: Vaccination Schedules

Study	Pentacel	Control Vaccines	Concomitantly Administered Vaccines
HCPDT: non-US licensed DTaP vaccine that is identical to the DTaP component of Pentacel vaccine. POLIOVAX: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur Limited. IPOL: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur SA.
* PCV7 manufactured by Wyeth Laboratories. † PCV7 was introduced after the study was initiated, and thus, administered concomitantly with Pentacel vaccine in a subset of participants. ‡ The first dose of hepatitis B vaccine (manufacturer not specified) was administered prior to study initiation, from birth to 21 days of age. Subsequent doses were with hepatitis B vaccine manufactured by Merck and Co. § MMR and varicella vaccines were both manufactured by Merck and Co. ¶ Study participants previously had received three doses of Pentacel vaccine by 8 months of age.
494-01	2, 4, 6 and 15 months	HCPDT + POLIOVAX + ActHIB at 2, 4, 6, and 15 months	7-valent pneumococcal conjugate vaccine* (PCV7) at 2, 4, and 6 months in a subset of participants†   Hepatitis B vaccine at 2 and 6 months‡
P3T06	2, 4, 6, and 15-16 months	DAPTACEL + IPOL + ActHIB at 2, 4, and 6 months; and DAPTACEL + ActHIB at 15-16 months	PCV7* at 2, 4, and 6 months   Hepatitis B vaccine at 2 and 6 months‡
494-03	2, 4, 6, and 15-16 months	None	PCV7* at 2, 4, and 6 months in all participants; and at 15 months in a random subset of participants   Hepatitis B vaccine at 2 and 6 months (if a dose was previously administered)‡ or at 2, 4, and 6 months (if no previous dose)   Measles, mumps, rubella vaccine§ (MMR) and varicella§ vaccine at 12 or 15 months in random subsets of participants
5A9908	15-18 months¶	None	None

Solicited Adverse Reactions

The incidence and severity of selected solicited injection site and systemic adverse reactions that occurred within 3 days following each dose of Pentacel or Control vaccines in Study P3T06 is shown in Table 2. Information on these reactions was recorded daily by parents or guardians on diary cards. In Table 2, injection site reactions are reported for the Pentacel vaccine and DAPTACEL vaccine injection sites.

Table 2: Number (Percentage) of Children with Selected Solicited Adverse Reactions by Severity Occurring within 0-3 days of Pentacel Vaccine or Control Vaccines in Study P3T06

* Any: Mild, Moderate or Severe; Mild: subject whimpers when site is touched; Moderate: subject cries when site is touched; Severe: subject cries when leg or arm is moved. † Fever is based upon actual temperatures recorded with no adjustments to the measurement route. ‡ Following Doses 1-3 combined, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 46.0%, 53.0%, 1.0%, and 0% respectively, for Pentacel vaccine and 44.8%, 54.0%, 1.0%, and 0.1%, respectively, for DAPTACEL + IPOL + ActHIB vaccines. Following Dose 4, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 62.7%, 34.4%, 2.4% and 0.5%, respectively, for Pentacel vaccine, and 61.1%, 36.6%, 1.7% and 0.5%, respectively, for DAPTACEL + ActHIB vaccines. § Moderate: interferes with or limits usual daily activity; Severe: disabling, not interested in usual daily activity.
Injection Site Reactions	Pentacel Vaccine				DAPTACEL Vaccine
	Dose 1 N = 465-467 %	Dose 2 N = 451 %	Dose 3 N = 438-440 %	Dose 4 N = 387-396 %	Dose 1 N = 1,400-1,404 %	Dose 2 N = 1,358-1,359 %	Dose 3 N = 1,311-1,312 %	Dose 4 N = 376-380 %
Redness
>5 mm	7.1	8.4	8.7	17.3	6.2	7.1	9.6	16.4
>25 mm	2.8	1.8	1.8	9.2	1.0	0.6	1.9	7.9
>50 mm	0.6	0.2	0.0	2.3	0.4	0.1	0.0	2.4
Swelling
>5 mm	7.5	7.3	5.0	9.7	4.0	4.0	6.5	10.3
>25 mm	3.0	2.0	1.6	3.8	1.6	0.7	1.1	4.0
>50 mm	0.9	0.0	0.0	0.8	0.4	0.1	0.1	1.3
Tenderness*
Any	47.5	39.2	42.7	56.1	48.8	38.2	40.9	51.1
Moderate or Severe	19.6	10.6	11.6	16.7	20.7	12.2	12.3	15.8
Severe	5.4	1.6	1.4	3.3	4.1	2.3	1.7	2.4
Increase in Arm Circumference
>5 mm				33.6				30.6
>20 mm	–	–	–	4.7	–	–	–	6.9
>40 mm				0.5				0.8
Systemic Reactions	Pentacel Vaccine				DAPTACEL + IPOL + ActHIB Vaccines			DAPTACEL + ActHIB Vaccines
	Dose 1 N = 466-467 %	Dose 2 N = 451-452 %	Dose 3 N = 435-440 %	Dose 4 N = 389-398 %	Dose 1 N = 1,390-1,406 %	Dose 2 N = 1,346-1,360 %	Dose 3 N = 1,301-1,312 %	Dose 4 N = 379-381 %
Fever†‡
≥38.0°C	5.8	10.9	16.3	13.4	9.3	16.1	15.8	8.7
>38.5°C	1.3	2.4	4.4	5.1	1.6	4.3	5.1	3.2
>39.5°C	0.4	0.0	0.7	0.3	0.1	0.4	0.3	0.8
Decreased Activity/Lethargy§
Any	45.8	32.7	32.5	24.1	51.1	37.4	33.2	24.1
Moderate or Severe	22.9	12.4	12.7	9.8	24.3	15.8	12.7	9.2
Severe	2.1	0.7	0.2	2.5	1.2	1.4	0.6	0.3
Inconsolable Crying
Any	59.3	49.8	47.3	35.9	58.5	51.4	47.9	36.2
≥1 hour	19.7	10.6	13.6	11.8	16.4	16.0	12.2	10.5
>3 hours	1.9	0.9	1.1	2.3	2.2	3.4	1.4	1.8
Fussiness/Irritability
Any	76.9	71.2	68.0	53.5	75.8	70.7	67.1	53.8
≥1 hour	34.5	27.0	26.4	23.6	33.3	30.5	26.2	19.4
>3 hours	4.3	4.0	5.0	5.3	5.6	5.5	4.3	4.5

Hypotonic Hyporesponsive Episodes

In Study P3T06, the diary cards included questions pertaining to HHEs. In Studies 494-01, 494-03, and 5A9908, a question about the occurrence of fainting or change in mental status was asked during post-vaccination phone calls. Across these 4 studies, no HHEs, as defined in a report of a US Public Health Service workshop (3) were reported among participants who received Pentacel vaccine (N = 5,979), separately administered HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032) or separately administered DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). Hypotonia not fulfilling HHE criteria within 7 days following vaccination was reported in 4 participants after the administration of Pentacel vaccine (1 on the same day as the 1st dose; 3 on the same day as the 3rd dose) and in 1 participant after the administration of DAPTACEL + IPOL + ActHIB vaccines (4 days following the 1st dose).

Seizures

Across Studies 494-01, 494-03, 5A9908 and P3T06, a total of 8 participants experienced a seizure within 7 days following either Pentacel vaccine (4 participants; N = 4,197 for at least one of Doses 1-3; N = 5,033 for Dose 4), separately administered HCPDT + POLIOVAX + ActHIB vaccines (3 participants; N = 1,032 for at least one of Doses 1-3, N = 739 for Dose 4), separately administered DAPTACEL + IPOL + ActHIB vaccines (1 participant; N = 1,455 for at least one of Doses 1-3), or separately administered DAPTACEL + ActHIB vaccines (0 participants; N = 418 for Dose 4). Among the four participants who experienced a seizure within 7 days following Pentacel vaccine, one participant in Study 494-01 had an afebrile seizure 6 days after the first dose, one participant in Study 494-01 had a possible seizure the same day as the third dose, and two participants in Study 5A9908 had a febrile seizure 2 and 4 days, respectively, after the fourth dose. Among the four participants who experienced a seizure within 7 days following Control vaccines, one participant had an afebrile seizure the same day as the first dose of DAPTACEL + IPOL + ActHIB vaccines, one participant had an afebrile seizure the same day as the second dose of HCPDT + POLIOVAX + ActHIB vaccines, and two participants had a febrile seizure 6 and 7 days, respectively, after the fourth dose of HCPDT + POLIOVAX + ActHIB vaccines.

Serious Adverse Events

In Study P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 19 of 484 (3.9%) participants who received Pentacel vaccine and 50 of 1,455 (3.4%) participants who received DAPTACEL + IPOL + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 5 of 431 (1.2%) participants who received Pentacel vaccine and 4 of 418 (1.0%) participants who received DAPTACEL + ActHIB vaccines experienced a serious adverse event. In Study 494-01, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 23 of 2,506 (0.9%) participants who received Pentacel vaccine and 11 of 1,032 (1.1%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 6 of 1,862 (0.3%) participants who received Pentacel vaccine and 2 of 739 (0.3%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event.

Across Studies 494-01, 494-03 and P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were bronchiolitis, dehydration, pneumonia and gastroenteritis. Across Studies 494-01, 494-03, 5A9908 and P3T06, within 30 days following Dose 4 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were dehydration, gastroenteritis, asthma, and pneumonia.

Across Studies 494-01, 494-03, 5A9908 and P3T06, two cases of encephalopathy were reported, both in participants who had received Pentacel vaccine (N = 5,979). One case occurred 30 days post-vaccination and was secondary to cardiac arrest following cardiac surgery. One infant who had onset of neurologic symptoms 8 days post-vaccination was subsequently found to have structural cerebral abnormalities and was diagnosed with congenital encephalopathy.

A total of 5 deaths occurred during Studies 494-01, 494-03, 5A9908 and P3T06: 4 in children who had received Pentacel vaccine (N = 5,979) and one in a participant who had received DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). There were no deaths reported in children who received HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032). Causes of death among children who received Pentacel vaccine were asphyxia due to suffocation, head trauma, Sudden Infant Death syndrome, and neuroblastoma (8, 23, 52 and 256 days post-vaccination, respectively). One participant with ependymoma died secondary to aspiration 222 days following DAPTACEL + IPOL + ActHIB vaccines.

. Data from Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of Pentacel vaccine worldwide, since 1997. Between 1997 and 2007, Pentacel vaccine was primarily used in Canada. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Pentacel vaccine.

• Cardiac disorders
  
  Cyanosis


• Gastrointestinal disorders
  
  Vomiting, diarrhea


• General disorders and administration site conditions
  
  Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H influenzae type b disease)


• Immune system disorders
  
  Hypersensitivity (such as rash and urticaria)


• Infections and infestations
  
  Meningitis, rhinitis, viral infection


• Metabolism and nutrition disorders
  
  Decreased appetite


• Nervous system disorders
  
  Somnolence, HHE, depressed level of consciousness


• Psychiatric disorders
  
  Screaming


• Respiratory, thoracic and mediastinal disorders
  
  Apnea, cough


• Skin and subcutaneous tissue disorders
  
  Erythema, skin discoloration


• Vascular disorders
  
  Pallor

7. DRUG INTERACTIONS

. Concomitant Administration with Other Vaccines

In clinical trials, Pentacel vaccine was administered concomitantly with one or more of the following US licensed vaccines: hepatitis B vaccine, 7-valent pneumococcal conjugate vaccine, MMR and varicella vaccines. [See Adverse Reactions (6) and Clinical Studies (14).] When Pentacel vaccine is given at the same time as another injectable vaccine(s), the vaccine(s) should be administered with different syringes and at different injection sites.

. Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Pentacel vaccine. [See Warnings and Precautions (5.6).]

. Drug/Laboratory Test Interactions

Antigenuria has been detected in some instances following receipt of ActHIB vaccine. Urine antigen detection may not have definite diagnostic value in suspected H influenzae type b disease within one week following receipt of Pentacel vaccine. (4)

8. USE IN SPECIFIC POPULATIONS

. Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Pentacel vaccine. It is also not known whether Pentacel vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

. Pediatric Use

The safety and effectiveness of Pentacel vaccine was established in the age group 6 weeks through 18 months on the basis of clinical studies. [See Adverse Reactions (6.1) and Clinical Studies (14).] The safety and effectiveness of Pentacel vaccine in the age group 19 months through 4 years is supported by evidence in children 6 weeks through 18 months. The safety and effectiveness of Pentacel vaccine in infants less than 6 weeks of age and in children 5 to 16 years of age have not been established.

11. DESCRIPTION

Pentacel vaccine consists of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus (DTaP-IPV) component and an ActHIB® vaccine component combined through reconstitution for intramuscular injection. ActHIB vaccine (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]), consists of H influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) covalently bound to tetanus toxoid (PRP-T). The DTaP-IPV component is supplied as a sterile liquid used to reconstitute the lyophilized ActHIB vaccine component to form Pentacel vaccine. Pentacel vaccine is a uniform, cloudy, white to off-white (yellow tinge) suspension.

Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)] and 10 mcg PRP of H influenzae type b covalently bound to 24 mcg of tetanus toxoid (PRP-T).

Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), ≤5 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.

Corynebacterium diphtheriae is grown in modified Mueller's growth medium. (5) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.

Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (6) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (7) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (8) (9) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the DTaP-IPV component is diluted to its final concentration. The DTaP-IPV component does not contain a preservative.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The immunogenicity of the inactivated polioviruses is evaluated by the antibody response in monkeys measured by virus neutralization.

PRP, a high molecular weight polymer, is prepared from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium. (10) The tetanus toxoid for conjugation to PRP is prepared by ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (11) The toxoid is filter sterilized prior to the conjugation process. The ActHIB vaccine component does not contain a preservative. Potency of the ActHIB vaccine component is specified on each lot by limits on the content of PRP polysaccharide and protein per dose and the proportion of polysaccharide and protein that is characterized as high molecular weight conjugate.

The vial stoppers for the DTaP-IPV and ActHIB vaccine components of Pentacel vaccine do not contain natural latex rubber.

12. CLINICAL PHARMACOLOGY

. Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (12) Levels of 1.0 IU/mL have been associated with long-term protection. (13)

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (12) (14) A tetanus antitoxoid level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of Pentacel vaccine is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

Poliomyelitis

Polioviruses, of which there are three serotypes (Types 1, 2, and 3) are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis. (15)

Invasive Disease Due to H influenzae Type b

H influenzae type b can cause invasive disease such as meningitis and sepsis. Anti-PRP antibody has been shown to correlate with protection against invasive disease due to H influenzae type b.

Based on data from passive antibody studies (16) and an efficacy study with H influenzae type b polysaccharide vaccine in Finland, (17) a post-vaccination anti-PRP level of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with H influenzae type