Kinrix

diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine

Dosage Form: injection, suspension
FULL PRESCRIBING INFORMATION

Indications and Usage for Kinrix

A single dose of Kinrix® is indicated for active immunization against diphtheria, tetanus, pertussis, and poliomyelitis as the fifth dose in the diphtheria, tetanus, and acellular pertussis (DTaP) vaccine series and the fourth dose in the inactivated poliovirus vaccine (IPV) series in children 4 through 6 years of age whose previous DTaP vaccine doses have been with INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed) and/or PEDIARIX® [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine] for the first three doses and INFANRIX for the fourth dose.

Kinrix Dosage and Administration

Preparation for Administration

Shake vigorously to obtain a homogeneous, turbid, white suspension. Do not use if resuspension does not occur with vigorous shaking. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. After removal of the dose, any vaccine remaining in the vial should be discarded.

Recommended Dose and Schedule

Kinrix is to be administered as a 0.5-mL dose by intramuscular injection. The preferred site of administration is the deltoid muscle of the upper arm. Do not administer this product intravenously, intradermally, or subcutaneously.

Kinrix may be used for the fifth dose in the DTaP immunization series and the fourth dose in the IPV immunization series in children 4 through 6 years of age (prior to the seventh birthday) whose previous DTaP vaccine doses have been with INFANRIX and/or PEDIARIX for the first three doses and INFANRIX for the fourth dose [see Indications and Usage (1)].

Dosage Forms and Strengths

Kinrix is a suspension for injection available in 0.5-mL single-dose vials and prefilled TIP-LOK® syringes.

Contraindications

Hypersensitivity

Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any diphtheria toxoid, tetanus toxoid, pertussis- or poliovirus-containing vaccine, or to any component of Kinrix, including neomycin and polymyxin B, is a contraindication to administration of Kinrix [see Description (11)]. Because of the uncertainty as to which component of the vaccine might be responsible, no further vaccination with any of these components should be given. Alternatively, such individuals may be referred to an allergist for evaluation if immunization with any of these components is considered.

Encephalopathy

Encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of administration 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 Kinrix.

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 Kinrix. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.

Warnings and Precautions

Guillain-Barré Syndrome

If Guillain-Barré syndrome occurs within 6 weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give any tetanus toxoid-containing vaccine, including Kinrix, should be based on careful consideration of the potential benefits and possible risks. When a decision is made to withhold tetanus toxoid, other available vaccines should be given, as indicated.

Latex

  Kinrix is available in vials and 2 types of prefilled syringes. One type of prefilled syringe has a tip cap which may contain natural rubber latex and a plunger which does not contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex rubber. Use of these syringes may cause allergic reactions in latex sensitive individuals. The vial stopper does not contain latex. [See How Supplied/Storage and Handling (16).]

Adverse Events Following Prior Pertussis Vaccination

If any of the following events occur in temporal relation to receipt of a pertussis-containing vaccine, the decision to give any pertussis-containing vaccine, including Kinrix, should be based on careful consideration of the potential benefits and possible risks:

• Temperature of ≥40.5oC (105oF) within 48 hours not due to another identifiable cause;


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


• Persistent, inconsolable crying lasting ≥3 hours, occurring within 48 hours;


• Seizures with or without fever occurring within 3 days.

When a decision is made to withhold pertussis vaccination, other available vaccines should be given, as indicated.

Children at Risk for Seizures

For children at higher risk for seizures than the general population, an appropriate antipyretic may be administered at the time of vaccination with a pertussis-containing vaccine, including Kinrix, and for the ensuing 24 hours to reduce the possibility of post-vaccination fever.

Preventing and Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the patient’s immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice.

A total of 3,537 children were vaccinated with a single dose of Kinrix in 3 clinical trials. Of these, 381 children received a non-US formulation of Kinrix (containing ≤2.5 mg 2-phenoxyethanol per dose as preservative). The primary study (Study 048), conducted in the United States, was a randomized, controlled clinical trial in which children 4 to 6 years of age were vaccinated with Kinrix (N = 3,156) or control vaccines (INFANRIX and IPOL® vaccine [IPV, Sanofi Pasteur SA]; N = 1,053) as a fifth DTaP vaccine dose following 4 doses of INFANRIX and as a fourth IPV dose following 3 doses of IPOL. Subjects also received the second dose of US-licensed measles, mumps, and rubella (MMR) vaccine (Merck & Co., Inc.) administered concomitantly, at separate sites.

Data on adverse events were collected by parents/guardians using standardized forms for 4 consecutive days following vaccination with Kinrix or control vaccines (i.e., day of vaccination and the next 3 days). The reported frequencies of solicited local reactions and general adverse events in Study 048 are presented in Table 1.

In 3 studies (Study 046, 047, and 048), children were monitored for unsolicited adverse events, including serious adverse events, that occurred in the 31-day period following vaccination and in 2 studies (Study 047 and 048), parents/guardians were actively queried about changes in the child’s health status, including the occurrence of serious adverse events, through 6 months post-vaccination.

Table 1. Percentage of Children 4 to 6 Years of Age Reporting Solicited Local Reactions or General Adverse Events Within 4 Days of Vaccinationa With Kinrix or Separate Concomitant Administration of INFANRIX and IPV When Coadministered With MMR Vaccine (Study 048) (Total Vaccinated Cohort)

	Kinrix	INFANRIX + IPV
Localb	N = 3,121-3,128	N = 1,039-1,043
Pain, any	57.0c	53.3
Pain, grade 2 or 3d	13.7	12.0
Pain, grade 3d	1.6c	0.6
Redness, any	36.6	36.6
Redness, ≥50 mm	17.6	20.0
Redness, ≥110 mm	2.9	4.1
Arm circumference increase, any	36.0	37.8
Arm circumference increase, >20 mm	6.9	7.4
Arm circumference increase, >30 mm	2.4	3.2
Swelling, any	26.0	27.0
Swelling, ≥50 mm	10.2	11.5
Swelling, ≥110 mm	1.4	1.8
General	N = 3,037-3,120	N = 993-1,036
Drowsiness, any	19.1	17.5
Drowsiness, grade 3e	0.8	0.8
Fever, ≥99.5°F	16.0	14.8
Fever, >100.4°F	6.5c	4.4
Fever, >102.2°F	1.1	1.1
Fever, >104°F	0.1	0.0
Loss of appetite, any	15.5	16.0
Loss of appetite, grade 3f	0.8	0.6

IPV manufactured by Sanofi Pasteur SA. MMR vaccine manufactured by Merck & Co., Inc.

Total Vaccinated Cohort = all vaccinated subjects for whom safety data were available.

N = number of children with evaluable data for the events listed.

a Within 4 days of vaccination defined as day of vaccination and the next 3 days.

b Local reactions at the injection site for Kinrix or INFANRIX.

c Statistically higher than comparator group (P <0.05).

d Grade 2 defined as painful when the limb was moved; Grade 3 defined as preventing normal daily activities.

e Grade 3 defined as preventing normal daily activities.

f Grade 3 defined as not eating at all.

In Study 048, Kinrix was non-inferior to INFANRIX with regard to swelling that involved >50% of the injected upper arm length and that was associated with a >30 mm increase in mid-upper arm circumference within 4 days following vaccination (upper limit of two-sided 95% Confidence Interval for difference in percentage of Kinrix [0.6%, n = 20] minus INFANRIX [1.0%, n = 11] ≤2%).

Serious Adverse Events: Within the 31-day period following study vaccination in 3 studies (Study 046, 047, and 048), in which all subjects received concomitant MMR vaccine (US-licensed MMR vaccine [Merck & Co., Inc.] in Study 047 and 048; non-US-licensed MMR vaccine in Study 046), 3 subjects (0.1% [3/3,537]) who received Kinrix reported serious adverse events (dehydration and hypernatremia; cerebrovascular accident; dehydration and gastroenteritis) and 4 subjects (0.3% [4/1,434]) who received INFANRIX and IPV (Sanofi Pasteur SA) reported serious adverse events (cellulitis; constipation; foreign body trauma; fever without identified etiology).

Postmarketing Experience

In addition to reports in clinical trials, the following adverse events, for which a causal relationship to components of Kinrix is plausible, have been reported since market introduction of DTaP-IPV manufactured by GlaxoSmithKline outside the U.S. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

General Disorders and Administration Site Conditions: Injection site vesicles.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Additional adverse events reported following postmarketing use of INFANRIX, for which a causal relationship to vaccination is plausible, are: Allergic reactions, including anaphylactoid reactions, anaphylaxis, angioedema, and urticaria, apnea, collapse or shock-like state (hypotonic-hyporesponsive episode), convulsions (with or without fever), lymphadenopathy, and thrombocytopenia.

Drug Interactions

Concomitant Vaccine Administration

In clinical trials, Kinrix was administered concomitantly with the second dose of MMR vaccine [see Clinical Studies (14)].

Data are not available on concomitant use of Kinrix and varicella vaccine.

When Kinrix is administered concomitantly with other injectable vaccines, they should be given with separate syringes. Kinrix should not be mixed with any other vaccine in the same syringe or vial.

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Kinrix.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

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

Pediatric Use

Safety and effectiveness of Kinrix in children younger than 4 years of age and children 7 to 16 years of age have not been evaluated. Kinrix is not approved for use in persons in these age groups.

Kinrix Description

Kinrix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine) is a noninfectious, sterile vaccine for intramuscular administration. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated pertussin toxin (PT), 25 mcg of filamentous hemagglutinin (FHA), 8 mcg of pertactin (69 kiloDalton outer membrane protein), 40 D-antigen Units (DU) of Type 1 poliovirus (Mahoney), 8 DU of Type 2 poliovirus (MEF-1), and 32 DU of Type 3 poliovirus (Saukett). The diphtheria, tetanus, and pertussis components of Kinrix are the same as those in INFANRIX and PEDIARIX and the poliovirus component is the same as that in PEDIARIX.

The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The bovine materials used in these extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.

The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.

Diphtheria and tetanus toxoids and pertussis antigens (inactivated PT, FHA, and pertactin) are individually adsorbed onto aluminum hydroxide.

The inactivated poliovirus component of Kinrix is an enhanced potency component. Each of the 3 strains of poliovirus is individually grown in VERO cells, a continuous line of monkey kidney cells, cultivated on microcarriers. Calf serum and lactalbumin hydrolysate are used during VERO cell culture and/or virus culture. Calf serum is sourced from countries the USDA has determined neither have nor are at risk of BSE. After clarification, each viral suspension is purified by ultrafiltration, diafiltration, and successive chromatographic steps, and inactivated with formaldehyde. The 3 purified viral strains are then pooled to form a trivalent concentrate.

Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components (inactivated PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. The potency of the inactivated poliovirus component is determined by using the D-antigen ELISA and by a poliovirus neutralizing cell culture assay on sera from previously immunized rats.

Each 0.5-mL dose contains aluminum hydroxide as adjuvant (not more than 0.6 mg aluminum by assay) and 4.5 mg of sodium chloride. Each dose also contains ≤100 mcg of residual formaldehyde and ≤100 mcg of polysorbate 80 (Tween 80). Neomycin sulfate and polymyxin B are used in the poliovirus vaccine manufacturing process and may be present in the final vaccine at ≤0.05 ng neomycin and ≤0.01 ng polymyxin B per dose.

Kinrix is available in vials and 2 types of prefilled syringes. One type of prefilled syringe has a tip cap which may contain natural rubber latex and a plunger which does not contain latex. The other type has a tip cap and a rubber plunger which contain dry natural latex rubber. The vial stopper does not contain latex. [See How Supplied/Storage and Handling (16).]

Kinrix does not contain a preservative.

Kinrix - Clinical Pharmacology

Mechanism of Action

Diphtheria: Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.1

Tetanus: Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2,3 A level of ≥0.1 IU/mL is considered protective.4

Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no well established serological correlate of protection for pertussis. The efficacy of the pertussis component of Kinrix was determined in clinical trials of INFANRIX administered as a 3-dose series in infants (see INFANRIX prescribing information).

Poliomyelitis: Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Neutralizing antibodies against the 3 poliovirus serotypes are recognized as conferring protection against poliomyelitis disease.5

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Kinrix has not been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

Clinical Studies

Immunological Evaluation

In a US multicenter study (Study 048), 4,209 children were randomized in a 3:1 ratio to receive either Kinrix or INFANRIX and IPV (Sanofi Pasteur SA) administered concomitantly at separate sites. Subjects also received MMR vaccine (Merck & Co., Inc.) administered concomitantly at a separate site. Subjects were children 4 through 6 years of age who previously received 4 doses of INFANRIX, 3 doses of IPV, and 1 dose of MMR vaccine. Among subjects in both vaccine groups combined, 49.6% were female; 45.6% of subjects were White, 18.8% Hispanic, 13.6% Asian, 7.0% Black, and 15.0% were of other racial/ethnic groups.

Levels of antibodies to the diphtheria, tetanus, pertussis (PT, FHA, and pertactin), and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 1 month (range 31 to 48 days) after vaccination (Table 2). The co-primary immunogenicity endpoints were anti-diphtheria toxoid, anti-tetanus toxoid, anti-PT, anti-FHA, and anti-pertactin booster responses, and anti-poliovirus Type 1, Type 2, and Type 3 geometric mean antibody titers (GMTs) 1 month after vaccination. Kinrix was shown to be non-inferior to INFANRIX and IPV administered separately, in terms of booster responses to DTaP antigens and post-vaccination GMTs for anti-poliovirus antibodies (Table 2).

Table 2. Pre-Vaccination Antibody Levels and Post-Vaccinationa Antibody Responses Following Kinrix Compared With Separate Concomitant Administration of INFANRIX and IPV in Children 4 to 6 Years of Age When Coadministered With MMR Vaccine (Study 048) (ATP Cohort for Immunogenicity)

	Kinrix	INFANRIX + IPV
	N = 787-851	N = 237-262
Anti-Diphtheria Toxoid
Pre-vaccination % ≥0.1 IU/mL (95% CI)b	87.7 (85.3, 89.9)	85.5 (80.6, 89.5)
Post-vaccination % ≥0.1 IU/mL (95% CI)b	100 (99.6, 100)	100 (98.6, 100)
% Booster Response (95% CI)c	99.5 (98.8, 99.9)d	100 (98.6, 100)
Anti-Tetanus Toxoid
Pre-vaccination % ≥0.1 IU/mL (95% CI)b	87.8 (85.4, 90.0)	88.2 (83.6, 91.8)
Post-vaccination % ≥0.1 IU/mL (95% CI)b	100 (99.6, 100)	100 (98.6, 100)
% Booster Response (95% CI)c	96.7 (95.2, 97.8)d	93.9 (90.2, 96.5)
Anti-PT
% Booster Response (95% CI)e	92.2 (90.2, 94.0)d	92.6 (88.7, 95.5)
Anti-FHA
% Booster Response (95% CI)e	95.4 (93.7, 96.7)d	96.2 (93.1, 98.1)
Anti-Pertactin
% Booster Response (95% CI)e	97.8 (96.5, 98.6)d	96.9 (94.1, 98.7)
Anti-Poliovirus 1
Pre-vaccination % ≥1:8 (95% CI)b	88.3 (85.9, 90.4)	85.1 (80.1, 89.2)
Post-vaccination % ≥1:8 (95% CI)b	99.9 (99.3, 100)	100 (98.5, 100)
Post-vaccination GMT (95% CI)	2,127 (1,976, 2,290)f	1,685 (1,475, 1,925)
Anti-Poliovirus 2
Pre-vaccination % ≥1:8 (95% CI)b	91.8 (89.7, 93.6)	87.0 (82.3, 90.8)
Post-vaccination % ≥1:8 (95% CI)b	100 (99.6, 100)	100 (98.5, 100)
Post-vaccination GMT (95% CI)	2,265 (2,114, 2,427)f	1,818 (1,606, 2,057)
Anti-Poliovirus 3
Pre-vaccination % ≥1:8 (95% CI)b	84.7 (82.0, 87.0)	85.0 (80.1, 89.1)
Post-vaccination % ≥1:8 (95% CI)b	100 (99.5, 100)	100 (98.5, 100)
Post-vaccination GMT (95% CI)	3,588 (3,345, 3,849)f	3,365 (2,961, 3,824)

IPV manufactured by Sanofi Pasteur SA. MMR vaccine manufactured by Merck & Co., Inc.

ATP = according-to-protocol; CI = Confidence Interval; GMT = geometric mean antibody titer

N = number of subjects with available results.

a One month blood sampling, range 31 to 48 days.

b Seroprotection defined as anti-diphtheria toxoid and anti-tetanus toxoid antibody concentrations ≥0.1 IU/mL by ELISA and as anti-poliovirus Type 1, Type 2, and Type 3 antibody titer ≥1:8 by micro-neutralization assay for poliovirus.

c Booster response: In subjects with pre-vaccination <0.1 IU/mL, post-vaccination concentration ≥0.4 IU/mL. In subjects with pre-vaccination concentration ≥0.1 IU/mL, an increase of at least 4 times the pre-vaccination concentration.

d Kinrix was non-inferior to INFANRIX + IPV based on booster response rates (upper limit of two-sided 95% CI on the difference of INFANRIX + IPV minus Kinrix ≤10%).

e Booster response: In subjects with pre-vaccination <5 EL.U./mL, post-vaccination concentration ≥20 EL.U./mL. In subjects with pre-vaccination ≥5 EL.U./mL and <20 EL.U./mL, an increase of at least 4 times the pre-vaccination concentration. In subjects with pre-vaccination ≥20 EL.U./mL, an increase of at least 2 times the pre-vaccination concentration.

f Kinrix was non-inferior to INFANRIX + IPV based on post-vaccination anti-poliovirus antibody GMTs adjusted for baseline titer (upper limit of two-sided 95% CI for the GMT ratio [INFANRIX + IPV:Kinrix] ≤1.5).

Concomitant Vaccine Administration

In a US study (Study 047), among recipients of DTaP-IPV (same formulation as Kinrix but also containing 2-phenoxyethanol) and the second dose of MMR vaccine (Merck & Co., Inc.) who had pre-vaccination sera tested for antibodies to measles, mumps, and rubella (N = 175-181), 99% of subjects were seropositive for antibodies to measles, mumps, and rubella prior to vaccination.

REFERENCES

1. Vitek CR and Wharton M. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:139-156.


2. Wassilak SGF, Roper MH, Kretsinger K, and Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:805-839.


3. Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review; Proposed rule. Federal Register December 13, 1985;50(240):51002-51117.


4. Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.


5. Sutter RW, Pallansch MA, Sawyer LA, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, Goldenthal KL, Burns DL, Lewis Jr BP, eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences; 1995:289-299.

How Supplied/Storage and Handling

Kinrix is available in 0.5-mL single-dose vials and disposable prefilled TIP-LOK syringes (packaged without needles):

NDC 58160-812-01 Vial (contains no latex) in Package of 10: NDC 58160-812-11

NDC 58160-812-43 Syringe (tip cap may contain latex; plunger contains no latex) in Package of 10: NDC 58160-812-52

NDC 58160-812-41 Syringe (tip cap and plunger contain latex) in Package of 5: NDC 58160-812-46

NDC 58160-812-41 Syringe (tip cap and plunger contain latex) in Package of 10: NDC 58160-812-51

Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen.

Patient Counseling Information

Parents or guardians should be:

• informed of the potential benefits and risks of immunization with Kinrix.


• informed about the potential for adverse reactions that have been temporally associated with administration of Kinrix or other vaccines containing similar components.


• instructed to report any adverse events to their healthcare provider.


• given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

INFANRIX, Kinrix, PEDIARIX, and TIP-LOK are registered trademarks of GlaxoSmithKline. IPOL is a registered trademark of Sanofi Pasteur Limited.

Manufactured by GlaxoSmithKline Biologicals

Rixensart, Belgium, US License 1617, and

Novartis Vaccines and Diagnostics GmbH & Co. KG

Marburg, Germany, US License 1754

Distributed by GlaxoSmithKline

Research Triangle Park, NC 27709

©2010, GlaxoSmithKline. All rights reserved.

August 2010

KNX:6PI

Principal Display Panel

NDC 58160-812-11

KinrixTM

Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine

DTaP-IPV

10 X 0.5 mL Single-Dose Vials

Store refrigerated between 2o and 8oC (36o and 46oF). Do not freeze. Discard if frozen.

Each 0.5 mL dose is formulated to contain 25 Lf diphtheria toxoid, 10 Lf tetanus toxoid, 25 mcg inactivated pertussis toxin, 25 mcg filamentous hemagglutinin, 8 mcg pertactin, 40 D-antigen Units (DU) Type 1 poliovirus, 8 DU Type 2 poliovirus, and 32 DU Type 3 poliovirus. Derived from C. diphtheriae, C. tetani, B. pertussis, and poliovirus strains Types 1, 2, and 3. Contains 4.5 mg sodium chloride and aluminum adjuvant (not more than 0.6 mg aluminum by assay). Inactivated with glutaraldehyde and formaldehyde. Each dose contains ≤0.05 ng neomycin sulfate and ≤0.01 ng polymyxin B. Contains no preservative. See complete prescribing information for additional details.

Do not dilute; shake well before using. For intramuscular administration only.

Dosage: 0.5 mL equals one dose. See complete prescribing information for vaccination schedule.

Kinrix is a trademark of GlaxoSmithKline.

U.S. License 1617

Manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium

Distributed by GlaxoSmithKline, Research Triangle Park, NC 27709

©2007, GlaxoSmithKline

Kinrix  diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine  injection, suspension

Product Information Product Type VACCINE NDC Product Code (Source) 58160-812 Route of Administration INTRAMUSCULAR DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) (CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED)) CORYNEBACTERIUM DIPHTHERIAE TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) 25 [iU]  in 0.5 mL CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) (CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED)) CLOSTRIDIUM TETANI TOXOID ANTIGEN (FORMALDEHYDE INACTIVATED) 10 [iU]  in 0.5 mL BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS FILAMENTOUS HEMAGGLUTININ ANTIGEN (FORMALDEHYDE INACTIVATED) 25 [iU]  in 0.5 mL BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS PERTACTIN ANTIGEN (FORMALDEHYDE INACTIVATED) 8 ug  in 0.5 mL BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED) (BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED)) BORDETELLA PERTUSSIS TOXOID ANTIGEN (FORMALDEHYDE, GLUTARALDEHYDE INACTIVATED) 25 ug  in 0.5 mL POLIOVIRUS TYPE 1 ANTIGEN (FORMALDEHYDE INACTIVATED) (POLIOVIRUS TYPE 1 ANTIGEN (FORMALDEHYDE INACTIVATED)) POLIOVIRUS TYPE 1 ANTIGEN (FORMALDEHYDE INACTIVATED) 40 [iU]  in 0.5 mL POLIOVIRUS TYPE 2 ANTIGEN (FORMALDEHYDE INACTIVATED) (POLIOVIRUS TYPE 2 ANTIGEN (FORMALDEHYDE INACTIVATED)) POLIOVIRUS TYPE 2 ANTIGEN (FORMALDEHYDE INACTIVATED) 8 [iU]  in 0.5 mL POLIOVIRUS TYPE 3 ANTIGEN (FORMALDEHYDE INACTIVATED) (POLIOVIRUS TYPE 3 ANTIGEN (FORMALDEHYDE INACTIVATED)) POLIOVIRUS TYPE 3 ANTIGEN (FORMALDEHYDE INACTIVATED) 32 [iU]  in 0.5 mL

Inactive Ingredients Ingredient Name Strength ALUMINUM HYDROXIDE   FORMALDEHYDE   NEOMYCIN SULFATE   POLYMYXIN B   POLYSORBATE 80   SODIUM CHLORIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58160-812-11 10 VIAL In 1 CARTON contains a VIAL (58160-812-01) 1 58160-812-01 0.5 mL In 1 VIAL This package is contained within the CARTON (58160-812-11) 2 58160-812-46 5 SYRINGE In 1 CARTON contains a SYRINGE (58160-812-41) 2 58160-812-41 0.5 mL In 1 SYRINGE This package is contained within the CARTON (58160-812-46) 3 58160-812-51 10 SYRINGE In 1 CARTON contains a SYRINGE 3 0.5 mL In 1 SYRINGE This package is contained within the CARTON (58160-812-51) 4 58160-812-52 10 SYRINGE In 1 CARTON contains a SYRINGE (58160-812-43) 4 58160-812-43 0.5 mL In 1 SYRINGE This package is contained within the CARTON (58160-812-52)

Marketing Information
Marketing Category

metformin and rosiglitazone

Generic Name: metformin and rosiglitazone (met FOR min and ROE zi GLI ta zone)

Brand Names: Avandamet

What is metformin and rosiglitazone?

Metformin and rosiglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Metformin and rosiglitazone is for people with type 2 diabetes who do not use daily insulin injections. This medication is not for treating type 1 diabetes.

Taking metformin and rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, metformin and rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Metformin and rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Metformin and rosiglitazone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about metformin and rosiglitazone?

Taking metformin and rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, metformin and rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

You should not use this medication if you are allergic to metformin (Glucophage) or rosiglitazone (Avandia), or if you advanced heart failure, kidney disease, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and rosiglitazone.

Before taking metformin and rosiglitazone, tell your doctor if you have congestive heart failure or heart disease, a history of heart attack or stroke, liver disease, or eye problems caused by diabetes.

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

What should I discuss with my healthcare provider before taking metformin and rosiglitazone?

Some people develop a life-threatening condition called lactic acidosis while taking metformin and rosiglitazone. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk. You should not use this medication if you are allergic to metformin (Glucophage) or rosiglitazone (Avandia), or if you have:

• 
  

  advanced heart failure; or

  
  


• 
  

  kidney disease;

  
  


• 
  

  if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

  
  

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and rosiglitazone.

To make sure you can safely take this medication, tell your doctor if you have congestive heart failure or heart disease, a history of heart attack or stroke, liver disease, or eye problems caused by diabetes.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes. FDA pregnancy category C. It is not known whether metformin and rosiglitazone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Some women using metformin and rosiglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control. Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking metformin and rosiglitazone. Talk with your doctor if you are concerned about this possibility. It is not known whether metformin and rosiglitazone passes into breast milk or if it could harm a nursing baby. Do not take metformin and rosiglitazone without first talking to your doctor if you are breast-feeding a baby.

How should I take metformin and rosiglitazone?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take metformin and rosiglitazone with meals, especially during the first few weeks of therapy.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, drink alcohol, or skip meals. These things can affect your glucose levels and your dose needs may also change.

Your doctor may want you to stop taking metformin and rosiglitazone for a short time if you become ill, have a fever or infection, or if you have surgery or a medical emergency.

Ask your doctor how to adjust your dose if needed. Do not change your medication dose or schedule without your doctor's advice.

Your doctor may have you take extra vitamin B12 while you are taking metformin and rosiglitazone. Take only the amount of vitamin B12 that your doctor has prescribed.

Store at room temperature away from moisture and heat.

See also: Metformin and rosiglitazone dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking metformin and rosiglitazone?

Avoid drinking alcohol. It can lower your blood sugar and may increase your risk of lactic acidosis while taking metformin and rosiglitazone.

Metformin and rosiglitazone side effects

This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or irregular heart rate, dizziness, or feeling very weak or tired. Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any other serious side effects, such as:

• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


• 
  

  sudden numbness, weakness, headache, confusion, or problems with vision, speech, or balance;

  
  


• 
  

  swelling or rapid weight gain, feeling short of breath, (even with mild exertion);

  
  


• 
  

  pale skin, feeling light-headed, rapid heart rate, trouble concentrating, fever, confusion or weakness;

  
  


• 
  

  severe blistering, peeling, and red skin rash; or

  
  


• 
  

  jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  headache, tired feeling;

  
  


• 
  

  nausea, vomiting, upset stomach, diarrhea; or

  
  


• 
  

  cold symptoms such as stuffy nose, sneezing, sore throat.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Metformin and rosiglitazone Dosing Information

Usual Adult Dose for Diabetes Mellitus Type II:

Doses are based on patient's current doses of rosiglitazone and/or metformin:

For patients inadequately controlled on metformin monotherapy: 4 mg rosiglitazone (total daily dose) plus the dose of metformin already being taken. If the patient was taking metformin 1000 mg/ day, the dose of metformin-rosiglitazone is 500 mg-2 mg orally twice daily. If the patient was taking metformin 2000 mg/day, the dose of metformin-rosiglitazone is 1000 mg-2 mg orally twice daily.

For patients inadequately controlled on rosiglitazone monotherapy: 1000 mg metformin (total daily dose) plus the dose of rosiglitazone already being taken. If the patient was taking rosiglitazone 4 mg/day, the dose of metformin-rosiglitazone is 500 mg-2 mg orally twice daily. If the patient was taking rosiglitazone 8 mg/day, the dose of metformin-rosiglitazone is 500 mg-4 mg orally twice daily.

What other drugs will affect metformin and rosiglitazone?

Tell your doctor about all other medicines you use, especially:

• 
  

  bosentan (Tracleer);

  
  


• 
  

  delavirdine (Rescriptor);

  
  


• 
  

  digoxin (Lanoxin);

  
  


• 
  

  gemfibrozil (Lopid);

  
  


• 
  

  morphine (MS Contin, Kadian, Oramorph);

  
  


• 
  

  tolbutamide (Orinase);

  
  


• 
  

  trimethoprim (Proloprim, Primsol, Bactrim, Cotrim, Septra);

  
  


• 
  

  vancomycin (Vancocin, Lyphocin);

  
  


• 
  

  amiloride (Midamor), furosemide (Lasix), or triamterene (Dyrenium);

  
  


• 
  

  cimetidine (Tagamet) or ranitidine (Zantac);

  
  


• 
  

  fluconazole (Diflucan) or ketoconazole (Nizoral);

  
  


• 
  

  nicardipine (Cardene) or nifedipine (Nifedical, Procardia);

  
  


• 
  

  procainamide (Procan, Pronestyl, Procanbid), quinidine (Quin-G), or quinine (Qualaquin);

  
  


• 
  

  rifampin (Rifater, Rifadin, Rifamate) or rifapentine (Priftin);

  
  


• 
  

  a non-steroidal anti-inflammatory drug (NSAID) such as flurbiprofen (Ansaid), ibuprofen (Advil, Motrin), indomethacin (Indocin), mefenamic acid (Ponstel), or piroxicam (Feldene); or

  
  


• 
  

  seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), phenobarbital (Solfoton), primidone (Mysoline), and others.

  
  

You may be more likely to have hyperglycemia (high blood sugar) if you are taking metformin and rosiglitazone with other drugs that raise blood sugar, such as:

• 
  

  isoniazid;

  
  


• 
  

  diuretics (water pills);

  
  


• 
  

  steroids (prednisone and others);

  
  


• 
  

  heart or blood pressure medication (Cartia, Cardizem, Covera, Isoptin, Verelan, and others);

  
  


• 
  

  niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);

  
  


• 
  

  phenothiazines (Compazine and others);

  
  


• 
  

  thyroid medicine (Synthroid and others);

  
  


• 
  

  birth control pills and other hormones;

  
  


• 
  

  seizure medicines (Dilantin and others); and

  
  


• 
  

  diet pills or medicines to treat asthma, colds or allergies.

  
  

These lists are not complete and there are many other medicines that can increase or decrease the effects of metformin and rosiglitazone on lowering your blood sugar. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More metformin and rosiglitazone resources

• Metformin and rosiglitazone Dosage
• Metformin and rosiglitazone Use in Pregnancy & Breastfeeding
• Metformin and rosiglitazone Drug Interactions
• Metformin and rosiglitazone Support Group
• 3 Reviews for Metformin and rosiglitazone - Add your own review/rating

Compare metformin and rosiglitazone with other medications

• Diabetes, Type 2

Where can I get more information?

• Your pharmacist can provide more information about metformin and rosiglitazone.

Fluvirin

Pronunciation: IN-floo-EN-za
Generic Name: Influenza Virus Vaccine
Brand Name: Fluvirin

Fluvirin is used for:

Protecting against certain strains of influenza (flu).

Fluvirin is a vaccine. It works by stimulating the body to produce antibodies against certain types of the flu virus, which helps your body to fight the infection.

Do NOT use Fluvirin if:

• you are allergic to any ingredient in Fluvirin, including eggs or egg products


• you have had a severe allergic reaction (eg, rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue) to a prior flu vaccination

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

Before using Fluvirin:

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

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


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


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


• if you are allergic to thimerosal (a preservative)


• if you have a fever, cold, respiratory tract infection, or other infection or recent illness


• if you have asthma or other breathing problems, a nervous system disorder, or blood or bleeding problems (eg, hemophilia, low blood platelet levels)


• if you have cancer or immune system problems (eg, HIV, weakened immune system)


• if you are receiving radiation treatment or chemotherapy


• if you have a history of Guillain-Barré syndrome

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

• Anticoagulants (eg, warfarin) because the risk of bleeding at the injection site may be increased


• Corticosteroids (eg, prednisone) or other medicines that may weaken the immune system because they may decrease Fluvirin's effectiveness. Ask your doctor if you are unsure if any of your medicines may weaken the immune system

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

How to use Fluvirin:

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

• Fluvirin is usually given once a year in September, October, or November.


• Fluvirin is given as an injection at your doctor's office, hospital, or clinic. Contact your health care provider if you have any questions.


• Some children may need to receive more than 1 dose of Fluvirin. Be sure to follow the vaccination schedule provided by your doctor.


• Do not use Fluvirin if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• If you miss a dose of Fluvirin, contact your doctor right away.

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

Important safety information:

• If you have a fever, cold, respiratory tract infection, or other illness, contact your doctor before you receive Fluvirin. You may need to receive your injection at a later time.


• Fluvirin contains killed viruses. It cannot cause you to develop the flu.


• Fluvirin is not a cure for the flu. It must be given before you are exposed to the flu in order to be effective.


• Fluvirin is only effective for 1 flu season. You will need to receive the flu vaccine each year.


• Fluvirin is not effective against all strains of the flu virus. It may also not protect everyone who receives it.


• Fluvirin does not protect against other respiratory viruses.


• Tell your doctor if you will be receiving any other vaccines.


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


• Some of these products contain thimerosal (a preservative). If you have ever had an allergic reaction to thimerosal, ask your pharmacist if your product has thimerosal in it.


• Use Fluvirin with caution in the ELDERLY; its effectiveness may be decreased in elderly patients.


• Fluvirin should not be used in CHILDREN younger than 4 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Fluvirin while you are pregnant. It is not known if Fluvirin is found in breast milk. If you are or will be breast-feeding while you use Fluvirin, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Fluvirin:

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

Back pain; chills; cough; fatigue; general body discomfort; headache; mild fever; mild pain, redness, swelling, or tenderness at the injection site; muscle or joint aches or pain; nausea; sore throat; stuffy nose; sweating; tiredness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness; wheezing); decreased movement of the face muscles; decreased movement or sensation in the arm or shoulder; dizziness; loss of appetite; muscle weakness; numbness or tingling of the hands or feet; red, swollen, blistered, or peeling skin; seizures; severe or persistent headache or fever; vision changes; vomiting.

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

See also: Fluvirin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Fluvirin:

Fluvirin is usually handled and stored by a health care provider. If you are using Fluvirin at home, store Fluvirin as directed by your pharmacist or health care provider. Keep this product, as well as syringes and needles, out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Fluvirin resources

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

• Fluvirin Prescribing Information (FDA)


• Fluvirin Advanced Consumer (Micromedex) - Includes Dosage Information


• Afluria Prescribing Information (FDA)


• Afluria Consumer Overview


• Agriflu Consumer Overview


• FluLaval Consumer Overview


• Fluarix Consumer Overview


• Fluarix Prescribing Information (FDA)


• Flulaval Prescribing Information (FDA)


• Fluzone Prescribing Information (FDA)


• Influenza Virus Vaccine Inactivated Monograph (AHFS DI)


• Influenza Virus Vaccine Live Intranasal Monograph (AHFS DI)

Compare Fluvirin with other medications

• Influenza Prophylaxis

cyclobenzaprine

sye-kloe-BEN-za-preen

Commonly used brand name(s)

In the U.S.

• Amrix


• Fexmid


• Flexeril


• FusePaq Tabradol

Available Dosage Forms:

• Capsule, Extended Release


• Tablet


• Suspension

Therapeutic Class: Skeletal Muscle Relaxant, Centrally Acting

Uses For cyclobenzaprine

Cyclobenzaprine is used to help relax certain muscles in your body. It helps relieve the pain, stiffness, and discomfort caused by strains, sprains, or injuries to your muscles. However, cyclobenzaprine does not take the place of rest, exercise or physical therapy, or other treatment that your doctor may recommend for your medical problem. Cyclobenzaprine acts on the central nervous system (CNS) to produce its muscle relaxant effects. Its actions on the CNS may also cause some of cyclobenzaprine's side effects.

Cyclobenzaprine may also be used for other conditions as determined by your doctor.

Cyclobenzaprine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, cyclobenzaprine is used in certain patients with fibromyalgia syndrome (also called fibrositis or fibrositis syndrome).

Before Using cyclobenzaprine

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 cyclobenzaprine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to cyclobenzaprine 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

Studies on cyclobenzaprine have been done only in adult patients, and there is no specific information comparing use of cyclobenzaprine in children with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of cyclobenzaprine tablets in the elderly with use in other age groups.

Because of the possibility of higher blood levels in the elderly as compared to younger adults, use of cyclobenzaprine extended-release capsules is not recommended in the elderly .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

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 cyclobenzaprine, 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 cyclobenzaprine 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.

• Brofaromine


• Clorgyline


• Furazolidone


• Iproniazid


• Isocarboxazid


• Lazabemide


• Linezolid


• Moclobemide


• Nialamide


• Pargyline


• Phenelzine


• Procarbazine


• Rasagiline


• Selegiline


• Toloxatone


• Tranylcypromine

Using cyclobenzaprine 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.

• Duloxetine


• Tramadol

Using cyclobenzaprine 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.

• Escitalopram


• Fluoxetine

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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Glaucoma or


• Problems with urination—Cyclobenzaprine can make your condition worse.

• Heart or blood vessel disease or


• Overactive thyroid—The chance of side effects may be increased.

• Liver disease—Higher blood levels of cyclobenzaprine may occur, increasing the chance of side effects .

Proper Use of cyclobenzaprine

Take cyclobenzaprine only as directed by your doctor. Do not take more of it and do not take it more often than your doctor ordered. To do so may increase the chance of serious side effects.

Dosing

The dose of cyclobenzaprine 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 cyclobenzaprine. 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 relaxing stiff muscles:
  
  • For the oral dosage form (tablets):
    
    • Adults and teenagers 15 years of age and older—The usual dose is 10 milligrams (mg) three times a day. The largest amount should be no more than 60 mg (six 10-mg tablets) a day.
    
    
    • Children and teenagers up to 15 years of age—Dose must be determined by your doctor.
    
    
  
  
  • For the oral dosage form (extended-release capsules):
    
    • Adults—The usual dose is 15 mg once a day. Some patients may require up to 30 mg (one 30 mg capsule or two 15 mg capsules) per day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

Missed Dose

If you miss a dose of cyclobenzaprine, 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.

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using cyclobenzaprine

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

cyclobenzaprine will add to the effects of alcohol and other CNS depressants (medicines that slow down the nervous system, possibly causing drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; barbiturates; medicine for seizures; other muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using cyclobenzaprine.

You should NOT use the extended-release capsules if you have used an MAO inhibitor (MAOI) such as Eldepryl®, Marplan®, Nardil®, or Parnate® within the past 14 days .

cyclobenzaprine may cause some people to have blurred vision or to become drowsy, dizzy, or less alert than they are normally. Make sure you know how you react to cyclobenzaprine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert and able to see well.

Cyclobenzaprine may cause dryness of the mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

If your condition does not improve within two or three weeks, or if it becomes worse, check with your doctor .

cyclobenzaprine 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.

Stop taking cyclobenzaprine and get emergency help immediately if any of the following effects occur:

Rare

• Changes in the skin color of the face


• fast or irregular breathing


• large swellings that look like hives on the face, eyelids, mouth, lips, and/or tongue


• puffiness or swelling of the eyelids or the area around the eyes


• shortness of breath, troubled breathing, tightness in chest, and/or wheezing


• skin rash, hives, or itching

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

Rare

• Fainting

Symptoms of overdose

• Convulsions (seizures)


• drowsiness (severe)


• dry, hot, flushed skin


• fast or irregular heartbeat


• hallucinations (seeing, hearing, or feeling things that are not there)


• increase or decrease in body temperature


• troubled breathing


• unexplained muscle stiffness


• unusual nervousness or restlessness (severe)


• vomiting (occurring together with other symptoms of overdose)

Check with your doctor as soon as possible if any of the following side effects occur:

Rare

• Clumsiness or unsteadiness


• confusion


• mental depression or other mood or mental changes


• problems in urinating


• ringing or buzzing in the ears


• skin rash, hives, or itching occurring without other symptoms of an allergic reaction listed above


• unusual thoughts or dreams


• yellow eyes or skin

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

• Blurred vision


• dizziness or lightheadedness


• drowsiness


• dryness of mouth

Less common or rare

• Bloated feeling or gas, indigestion, nausea or vomiting, or stomach cramps or pain


• constipation


• diarrhea


• excitement or nervousness


• frequent urination


• general feeling of discomfort or illness


• headache


• muscle twitching


• numbness, tingling, pain, or weakness in hands or feet


• pounding heartbeat


• problems in speaking


• trembling


• trouble in sleeping


• unpleasant taste or other taste changes


• unusual muscle weakness


• unusual tiredness

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: cyclobenzaprine 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 cyclobenzaprine resources

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

• Cyclobenzaprine Prescribing Information (FDA)


• Cyclobenzaprine MedFacts Consumer Leaflet (Wolters Kluwer)


• Cyclobenzaprine Monograph (AHFS DI)


• Amrix Prescribing Information (FDA)


• Amrix Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Fexmid Prescribing Information (FDA)


• Flexeril Prescribing Information (FDA)


• Flexeril Consumer Overview

Compare cyclobenzaprine with other medications

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Propain Plus

1. Name Of The Medicinal Product

Sedinol, Painex, Propain Plus or Feminax Plus Period Pain Caplets

2. Qualitative And Quantitative Composition

Paracetamol BP 450mg

Doxylamine Succinate USP 5mg

Caffeine Anhydrous BP 30mg

Codeine Phosphate BP 10mg

For excipients see 6.1

3. Pharmaceutical Form

Tablet (capsule shaped tablet – caplet).

4. Clinical Particulars

4.1 Therapeutic Indications

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone of the following conditions:

Treatment of tension headache, headache, toothache, backache, migraine, neuralgia, dysmenorrhoea, muscular and rheumatic aches and pains, post-operative analgesia following surgical and dental procedures.

4.2 Posology And Method Of Administration

Adults and children over 12 years: One to two tablets every 4-6 hours. Not suitable for children under 12 years of age.

Elderly: Dosage as for adults.

Do not exceed 8 tablets per 24 hours.

Do not take for more than 3 days continuously without medical review.

Route of Administration: Oral.

4.3 Contraindications

Sensitivity to paracetamol, doxylamine succinate, codeine phosphate, caffeine or any of the other ingredients in the product.

4.4 Special Warnings And Precautions For Use

Should be taken only with caution by asthmatics.

This medicine may lead to drowsiness and impaired concentration, which may be aggravated by simultaneous intake of alcohol or other central nervous system depressant agents. Patients should be warned against taking charge of vehicles or machinery or performing potentially hazardous tasks where loss of concentration may lead to accidents.

Dosage in excess of those recommended may cause severe liver damage.

Care is advised in the administration of paracetamol-containing product to patients with severe renal or severe hepatic impairment and in those with non-cirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease. Patients suffering from liver or kidney disease should take paracetamol under medical supervision. The dosage in renal impairment must be reduced.

The elderly are more likely to metabolise or eliminate opioid analgesics more slowly than young adults.

Codeine may cause faecal impaction, producing incontinence, spurious diarrhoea, abdominal pain and rarely colonic obstruction.

Dependence can develop with repeated use of codeine and therefore withdrawal symptoms may appear if the product is withdrawn abruptly.

Caution is advised when treating patients with hypertension, hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock, obstructive bowel disorders, acute abdominal conditions, recent gastrointestinal surgery, gallstones, a history of cardiac arrhythmias or convulsions. Care should be taken with patients with a history of drug abuse or emotional instability.

Patients should be warned of the following via the label and leaflet:

• Do not exceed the recommended dose.

• Do not take any other paracetamol-containing products.

• Consult your doctor if no relief is obtained with the recommended dosage.

• Keep out of the reach of children.

• This product contains paracetamol.

• Immediate medical advice should be sought in the event of an overdose even if you feel well due to the risk of severe liver damage.

• Alcoholic drink should be avoided.

The leaflet will state:

Headlines section (to be prominently displayed)

• This medicine can only be used for …….(indications)

• You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice

• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take this medicine for headaches for more than three days it can make them worse

Section 1: What the medicine is for

• Succinct description of the indications from 4.1 of the SmPC Section 2: Before taking

• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take a painkiller for headaches for more than three days it can make them worse

Section 3: Dosage

• Do not take for more than 3 days. If you need to use this medicine for more than three days you must speak to your doctor or pharmacist

• This medicine contains codeine and can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

Section 4: Side effects

• Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday – Friday) or fill in a paper form available from your local pharmacy.

How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

• You need to take the medicine for longer periods of time

• You need to take more than the recommended dose

• When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

The label will state (prominently but not in a box):

Front of Pack

• Can cause addiction

• For three days use only

Back of Pack

• List of indications as agreed in 4.1 of the SmPC

• If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist

• This medicine contains codeine [or dihydrocodeine] which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paracetamol:

The gastro-intestinal absorption of paracetamol may be delayed by drugs such as anticholinergic agents or opioid analgesics which decrease gastric emptying. Colestyramine may reduce the absorption of paracetamol. Metoclopramide and domperidone may potentiate the speed of absorption of paracetamol.

The likelihood of toxicity may be increased by the concomitant use of enzyme-inducing agents such as alcohol, anti-epileptics, barbiturates and tricyclic antidepressants.

Repeated doses of paracetamol increase the anticoagulant response to coumarins.

Paracetamol with aspirin has been noted to increase the blood concentration of unhydrolysed aspirin.

Doxylamine Succinate:

The antihistamines can enhance the sedative effect of central nervous system depressants, including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives and tranquillisers. The effects of the anticholinergic drugs such as atropine and tricyclic antidepressants may be enhanced. MAOI's may enhance the antimuscarinic effects of antihistamines

Caffeine:

Caffeine enhances the action of the ergot alkaloids in the treatment of migraine. Small doses of caffeine (5 to 10mg/kg) also appear to reduce the ED 50 for aspirin, indometacin and phenylbutazone by more than threefold.

Codeine Phosphate:

The depressant effects of some of the opioids may be exaggerated and prolonged by phenothiazines, monoamine oxidase inhibitors and tricyclic antidepressants. Codeine may cause a hypotensive or hypertensive effect if used with MAOI's. Concomitant use should be avoided and codeine should not be administered until 2 weeks after MAOI's are discontinued.

Alcohol, antipsychotics, anxiolytics and hypnotics may enhance the sedative and hypotensive effects of codeine.

When codeine is given with cisapride, metoclopramide or domperidone, the gut motility properties of these drugs may be lessened due to the constipating effect of codeine.

Cimetidine may inhibit the metabolism of opiates.

The absorption of mexiletine may be delayed by codeine and as such the anti-arrhythmic effect may be lessened.

Naltrexone and naloxone antagonise the analgesic, CNS and respiratory depressant effect of opioids.

The hypotensive action of diuretics and antihypertensives may be potentiated by codeine.

Use of antidiarrhoeals and antiperistaltic drugs such as loperamide may induce severe constipation. Concurrent use of antimuscarinics may lead to a greater risk of severe constipation which subsequently causes paralytic ileus and/or urinary retention.

4.6 Pregnancy And Lactation

No data is available on the use of these tablets in human pregnancy or on the excretion of it or its metabolites in human milk. Therefore this product is not recommended for use during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

Caution is advised as this medicine may lead to drowsiness and impaired concentration aggravated by simultaneous intake of alcohol or other central nervous system depressant agents.

4.8 Undesirable Effects

In recommended therapeutic dosage, paracetamol is actually well tolerated. Skin rash and other allergic reactions occur occasionally. The rash is usually erythematous or urticarial, but sometimes more serious and may be accompanied by drug fever and mucosal lesions. In a few cases the use of paracetamol has been associated with the occurrence of thrombocytopenia, neutropenia, pancytopenia and leucopenia.

Acute pancreatitis has been reported after prolonged use of paracetamol.

Side effects of the antihistamines vary in incidence and severity with each patient as much as with each drug. The most common effect is sedation. Other side-effects include gastro-intestinal disturbances, headache, blurred vision, tinnitus, elation or depression, irritability, nightmares, anorexia, difficulty in micturition, dryness of the mouth, tightness of the chest, and tingling, heaviness and weakness of the hands.

Side effects of caffeine include nausea, headache and insomnia. Large doses may cause restlessness, excitement, muscle tremor, tinnitus, scintillating scotoma, tachycardia and extrasystoles. Caffeine increases gastric secretion and may cause gastric ulceration.

The commonest side effects of therapeutic doses of codeine are constipation, nausea and vomiting, dizziness, drowsiness, respiratory depression and hypotension, but these are less common than with morphine. Very rarely skin rashes may occur in patients hypersensitive to codeine. Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped. Prolonged use of a painkiller for headaches can make them worse.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

If the patient

a, Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b, Regularly consumes ethanol in excess of recommended amounts.

Or

c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.

Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management

This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: N02B E51

The tablets have analgesic, antipyretic and antihistaminic action.

5.2 Pharmacokinetic Properties

Paracetamol, doxylamine succinate, caffeine anhydrous and codeine phosphate, the active ingredients in these tablets, are well known and documented, and have been used in therapeutics for many years.

Paracetamol is absorbed via the gastrointestinal tract with peak plasma levels occurring within 10 to 60 minutes. Paracetamol is distributed throughout the body into the majority of body tissues. Metabolism occurs mainly in the liver and is excreted via the urine as glucuronide and sulphate conjugates. Excretion of unchanged paracetamol is less than 5%. The elimination half life is between 1 – 3 hours.

Doxylamine Succinate is absorbed with peak plasma concentrations occurring within 2 to 3 hours. The elimination half life is about 10 hours.

Caffeine is rapidly absorbed with peak plasma concentrations occurring between 5 and 60 minutes following oral administration. It is widely distributed throughout the body. Caffeine is metabolised by the liver and excreted as metabolites in the urine with only 1% as unchanged caffeine. In adults the elimination half life is about 3 – 7 hours.

Codeine is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring at about 60 minutes. Codeine is metabolised hepatically and excreted via the urine mainly as conjugates and glucuronic acid. The elimination half life is between 3 and 4 hours.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Povidone K25

Maize starch (dried)

Magnesium Stearate

Colloidal Silicon Dioxide

Microcrystalline Cellulose

Hypromellose

Hydroxypropyl Cellulose

Glycerol

Carnauba Wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

PVC (250μm) and foil (20μm) 'Blister Pack'. Pack sizes: 8, 10, 16, 20, 32.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0363

9. Date Of First Authorisation/Renewal Of The Authorisation

05 January 2000 / 06 March 2009

10. Date Of Revision Of The Text

23/12/2009