Menomune

neisseria meningitidis group a polysaccharide antigen, a, neisseria meningitidis group c polysaccharide antigen, a, neisseria meningitidis group y polysaccharide antigen, a and neisseria meningitidis group w-135 polysaccharide antigen, a

Dosage Form: injection
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Menomune® – A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined, is indicated for active immunization for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135. Menomune – A/C/Y/W-135 vaccine is approved for use in persons 2 years of age and older.

Menomune – A/C/Y/W-135 vaccine is not indicated for the prevention of meningitis caused by microorganisms other than N. meningitidis serogroups A, C, Y, and W-135. Menomune – A/C/Y/W-135 vaccine is not indicated for treatment of meningococcal infections.

2. DOSAGE AND ADMINISTRATION

. Administration

The lyophilized vaccine should be a white or off-white color to a light beige color. The diluent used for reconstitution is a clear liquid.

Using a suitable size syringe, withdraw the supplied diluent (0.6 mL for single-dose presentation and 6.0 mL for multidose presentation) and inject into the vial containing the lyophilized vaccine. Swirl the vial until the vaccine is thoroughly dissolved. When reconstituted, the vaccine should be a clear, colorless liquid.

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 exist, the vaccine should not be administered.

Withdraw and administer a 0.5 mL dose of Menomune – A/C/Y/W-135 vaccine by subcutaneous injection.

Vaccine supplied in single dose vials should be used immediately after reconstitution.

Vaccine supplied in multidose vials may be used for up to 35 days after reconstitution if stored at 2° to 8°C (35° to 46°F). [See How Supplied/Storage and Handling (16.2).]

. Primary Immunization

Primary immunization with Menomune – A/C/Y/W-135 vaccine consists of a single 0.5mL dose administered subcutaneously. The preferred site of administration is the deltoid region.

The ACIP (Advisory Committee on Immunization Practices) has specfic recommendations for use of meningococcal vaccines. (1) (2) (3)

. Revaccination

The ACIP has recommendations for revaccination against meningococcal disease for persons at high risk who were previously vaccinated with Menomune – A/C/Y/W-135 vaccine. (1) (3) If Menomune – A/C/Y/W-135 vaccine is used for revaccination, the dose is 0.5mL administered subcutaneously.

3. DOSAGE FORMS AND STRENGTHS

Menomune – A/C/Y/W-135 vaccine is supplied as a lyophilized vaccine, in a single dose or a multidose (10 dose) vial, with corresponding single dose or multidose vial of diluent. The lyophilized vaccine is reconstituted with the diluent [see Dosage and Administration (2.1)]. After reconstitution, each dose consists of a 0.5mL suspension for injection. See Description (11) for the complete listing of ingredients.

4. CONTRAINDICATIONS

. Hypersensitivity

 Do not administer to anyone with a history of a severe allergic reaction (e.g., anaphylaxis) to Menomune – A/C/Y/W-135 vaccine or any component of the vaccine [see Description (11)].

5. WARNINGS AND PRECAUTIONS

. Latex

 The stoppers to the vials of lyophilized vaccine and diluent contain dry natural latex rubber that may cause allergic reactions in latex sensitive persons.

. Management of Acute Allergic Reactions

Appropriate medical treatment must be available to manage possible anaphylactic reactions following administration of the vaccine.

. Moderate or Severe Acute Illness

To avoid diagnostic confusion between manifestations of an acute illness and possible vaccine adverse effects, vaccination with Menomune – A/C/Y/W-135 vaccine should be postponed in persons with moderate or severe acute illness. (4)

. Limitations of Vaccine Effectivness

Menomune –A/C/Y/W-135 vaccine may not protect all recipients.

. Altered Immunocompetence

Persons who are immunosuppressed, including persons receiving immunosuppressive therapy, may have a diminished immune response to Menomune – A/C/Y/W-135 vaccine [see Drug Interactions(7)].

6. ADVERSE REACTIONS

. Data from Clinical Studies

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 clinical practice.

In three clinical trials primarily designed to assess the safety and immunogenicity of another vaccine, Menactra® [Meningococcal (Groups A, C, Y, W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], participants were randomized to receive Menactra or Menomune – A/C/Y/W-135 vaccine, which was used as a control vaccine. In these three trials, 1519 children 2-10 years of age, 972 persons 11-18 years of age, and 1170 adults 18-55 years of age, respectively, received a dose of Menomune – A/C/Y/W-135 vaccine. Overall, of the children 2-10 years of age who received Menactra or Menomune – A/C/Y/W-135 vaccine, 68% were enrolled at US sites and 32% were enrolled at a Chilean site. The median ages of US and Chilean children were 6 and 5 years, respectively; 50.5% were males; and 92.0% were Caucasian. Among participants 11–55 years of age who received Menactra or Menomune – A/C/Y/ W-135 vaccine, all were enrolled at US sites; 54.8% were female; 87.7% were Caucasian.

Solicited local and systemic reactions were monitored daily for 7 days post-vaccination using a diary card. Information on serious adverse events was collected at interim clinic visits and by telephone interview conducted 6 months post-vaccination. At least 94% of participants from the three studies completed the 6-month follow-up.

Serious Adverse Events

Across the three studies, serious adverse events within 6-months following Menomune – A/C/Y/W-135 vaccine were reported in 0.7% of 1519 children 2-10 years of age, 0.6% of 972 persons 11-18 years of age, and 1.7% of 1170 persons 18-55 years of age.

Solicited Adverse Events1

The most commonly reported solicited adverse events in US children 2-10 years of age were injection site pain, irritability and diarrhea. (Table 1)

The most commonly reported solicited adverse events in adolescents, ages 11 - 18 years, and adults, ages 18 - 55 years, were injection site pain, headache and fatigue. (Table 2)

Table 1: Percentage of US participants 2-10 years of age reporting solicited adverse events within 7 days following administration of Menomune - A/C/Y/W-135 vaccine

	N=1019-1027*
Event	Any	Moderate	Severe
	%	%	%
% is based on N.
* N = The total number of participants with data. The N is for 1027 participants for all solicited events except fever (N=1019). † Moderate: Discomforting, interfered with or limited usual arm movement, Severe: Disabling, child unable to move arm. ‡ Moderate: 1.0–2.0 inches; Severe: > 2.0 inches. § Oral equivalent temperature; Moderate: 38.4-39.4 ºC, Severe: ≥ 39.5ºC. ¶ Moderate: Skipped 2 meals, Severe: skipped ≥ 3 meals. # Moderate: 2 episodes, Severe: ≥ 3 episodes. Þ Moderate: 3-4 episodes, Severe: ≥ 5 episodes. ß Moderate: Interferes with normal activities, Severe: disabling, unwilling to engage in play or interaction with others. à Moderate: 1-3 hours duration, Severe: > 3 hours duration. è These solicited adverse events were reported as present or absent only. ð Moderate: Decreased range of motion due to pain or discomfort, Severe: unable to move major joints because of pain.
General Disorders and Administration Site Conditions
Injection site reaction
Pain †	26.1	2.5	0.0
Redness‡	7.9	0.5	0.0
Induration‡	4.2	0.6	0.0
Swelling‡	2.8	0.3	0.0
Systemic events
Fever §	5.2	1.7	0.2
Gastrointestinal disorders
Anorexia ¶	8.7	1.3	0.8
Vomiting #	2.7	0.7	0.6
Diarrhea Þ	11.8	2.5	0.3
Nervous system disorders
Drowsiness ß	11.2	2.5	0.5
Irritability à	12.2	2.6	0.6
Seizures è	0.0	N/A	N/A
Musculoskeletal and connective tissue disorders
Arthralgia ð	5.3	0.7	0.0
Skin and subcutaneous disorders
Rash è	3.0	N/A	N/A

Table 2: Percentage of participants 11-55 years of age reporting solicited adverse events within 7 days following administration of Menomune - A/C/Y/W-135 vaccine

	Study 1 N*=970			Study 2 N*=1159
	Participants 11-18 years of age			Participants 18-55 years of age
Event	Any	Moderate	Severe	Any	Moderate	Severe
* N=Total number of participants with data. † Moderate: Discomforting, interfered with or limited usual arm movement, Severe: Disabling, unable to move arm. ‡ Moderate: 1.0–2.0 inches; Severe: > 2.0 inches. § Moderate: Interferes with normal activities, Severe: disabling, requires bed rest. ¶ Oral equivalent temperature. Study 1: Moderate: 38.5-39.4 ºC, Severe: ≥ 39.5ºC. Study 2: Moderate 39.0-39.9 ºC, Severe: ≥ 40.0 ºC. # Moderate: 3-4 episodes, Severe: ≥ 5 episodes. Þ Moderate: Skipped 2 meals, Severe: skipped ≥ 3 meals. ß Moderate: 2 episodes, Severe: ≥ 3 episodes. à Moderate: discomforting enough to interfere with activities, Severe: disabling requires bed rest and analgesics. è These solicited adverse events were reported as present or absent only.
General Disorders and Administration Site Conditions
Injection Site reaction
Pain†	28.7	2.6	0.0	48.1	3.3	0.1
Redness‡	5.7	0.4	0.0	16.0	1.9	0.1
Induration‡	5.2	0.5	0.0	11.0	1.0	0.0
Swelling‡	3.6	0.3	0.0	7.6	0.7	0.0
Systemic events
Fatigue§	25.1	6.2	0.2	32.3	6.6	0.4
Malaise§	16.8	3.4	0.4	22.3	4.7	0.9
Chills§	3.5	0.4	0.1	5.6	1.0	0.0
Fever¶	3.0	0.3	0.1	0.5	0.1	0.0
Gastrointestinal disorders
Diarrhea#	10.2	1.3	0.0	14.0	2.9	0.3
AnorexiaÞ	7.7	1.1	0.2	9.9	1.6	0.4
Vomitingß	1.4	0.5	0.3	1.5	0.2	0.4
Nervous system disorders
Headacheà	29.3	6.5	0.4	41.8	8.9	0.9
Seizureè	0.0	N/A	N/A	0.0	N/A	N/A
Musculoskeletal and connective tissue disorders
Arthralgia§	10.2	2.1	0.1	16.0	2.6	0.1
Skin and subcutaneous disorders
Rashè	1.4	N/A	N/A	0.8	N/A	N/A

1

Events in Table 1 and Table 2 were collected in the clinical trials under "Solicited local and systemic reactions".

. Data from Post-Marketing Experience

The following adverse events have been spontaneously reported during post-approval use of Menomune – A/C/Y/W-135 vaccine since 1993 through November 2008. Because these events were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to Menomune – A/C/Y/W-135 vaccine exposure.

The following adverse events were included based on severity, frequency of reporting or the strength of causal association to Menomune – A/C/Y/W-135 vaccine.

• Immune system disorders
  

   

  
  

  Hypersensitivity, such as rash, urticaria, pruritus, dyspnoea, angioedema.

  
  



• Nervous System Disorders
  

   

  
  

  Headache, vasovagal syncope, dizziness, paraesthesia, Guillain-Barré syndrome

  
  



• Gastrointestinal disorders
  

   

  
  

  Nausea, vomiting, diarrhea

  
  



• Musculoskeletal and Connective Tissue Disorders
  

   

  
  

  Myalgia, arthralgia

  
  



• General Disorders and Administration Site Conditions
  

   

  
  

  Fever, injection site reaction, malaise, asthenia, chills, fatigue

  
  

7. DRUG INTERACTIONS

Do not mix Menomune – A/C/Y/W-135 vaccine with other vaccines in the same syringe or vial.

Immunosuppressive therapies may reduce the immune response to Menomune – A/C/Y/W-135 vaccine.

No safety and immunogenicity data are available on the concomitant administration of Menomune – A/C/Y/W-135 vaccine with other US licensed vaccines.

8. USE IN SPECIFIC POPULATIONS

. Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Menomune – A/C/Y/W-135 vaccine. It is also not known whether Menomune – A/C/Y/W-135 vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Menomune – A/C/Y/W-135 vaccine should be given to a pregnant woman only if clearly needed.

. Nursing Mothers

It is not known whether Menomune – A/C/Y/W-135 vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Menomune – A/C/Y/W-135 vaccine is administered to a nursing woman.

. Pediatric Use

Safety and effectiveness of Menomune – A/C/Y/W-135 vaccine in children below the age of 2 years have not been established.

During a meningococcal serogroup A epidemic in sub-Saharan Africa, children 3 months to 16 years of age were vaccinated with a high molecular weight serogroup A/C meningococcal polysaccharide vaccine. In case-control studies, after 1 year of observation, vaccine efficacy against meningococcal serogroup A disease was estimated to be 87% [(90% Confidence Interval (CI), 52% to 96%], overall. After 3 years, efficacy was estimated to be 67% (90% CI, 40% to 82%) among children who were 4-16 years of age at the time of vaccination and 8% (90% CI, -102% to 58%) among children who were 1-3 years of age at the time of vaccination. (5)

The efficacy of a serogroup C meningococcal vaccine in infants and young children was evaluated in a placebo-controlled trial during a serogroup C epidemic in Brazil. Vaccine efficacy was estimated to be 12% (95% CI, -55% to 62%) among children 6 to 23 months of age and 55% (95% CI, -4% to 72%) among children 24 to 36 months of age. (6)

Geriatric Use

Clinical studies of Menomune - A/C/Y/W-135 vaccine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

11. DESCRIPTION

Menomune – A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined, is a vaccine for subcutaneous injection. Menomune – A/C/Y/W-135 vaccine consists of a sterile lyophilized preparation of the group-specific polysaccharide antigens from N meningitidis, Group A, Group C, Group Y and Group W-135. N meningitidis are cultivated with Mueller Hinton agar (7) and Watson Scherp (8) media. The purified polysaccharide is extracted from the N meningitidis cells and separated from the media by procedures which include centrifugation, detergent precipitation, alcohol precipitation, solvent or organic extraction and diafiltration. No preservative is added during manufacture.

The diluent (0.6 mL) for the single –dose presentation contains sterile, pyrogen-free distilled water without preservative. The diluent (6 mL) for the multi-dose presentation contains sterile, pyrogen-free distilled water and thimerosal, a mercury derivative, which is added as a preservative for the reconstituted vaccine. [See How Supplied/Storage and Handling (16).]

After reconstitution with diluent the vaccine is a clear colorless liquid suspension. Each 0.5 mL dose contains 50 mcg of polysaccharide from each of serogroups A, C, Y and W-135. Reconstituted vaccine from a multi-dose vial also contains 25 mcg mercury per dose.

Each dose of vaccine contains 2.5 mg to 5 mg of lactose added as a stabilizer. (9)

Potency is evaluated by measuring the molecular size of each polysaccharide component using a column chromatography method as standardized by the US Food and Drug Administration (FDA) and the World Health Organization (WHO) (10) for Meningococcal Polysaccharide Vaccine.

12. CLINICAL PHARMACOLOGY

. Mechanism of Action

The presence of bactericidal anti-capsular meningococcal antibodies has been associated with protection from invasive meningococcal disease. (11) (12) Menomune – A/C/Y/W-135 vaccine induces the production of bactericidal antibodies specific to the capsular polysaccharides of serogroups A, C, Y and W-135.

13. NON-CLINICAL TOXICOLOGY

. Carcinogenesis, mutagenesis, impairment of fertility

Menomune – A/C/Y/W-135 vaccine has not been evaluated for carcinogenic or mutagenic potential or impairment of fertility.

14. CLINICAL STUDIES

Effectiveness of Menomune – A/C/Y/W-135 vaccine was inferred by evaluating the proportion of children 2-10 years of age achieving a pre-specified level of serum bactericidal antibody and the proportion of persons 11-55 years of age achieving a 4-fold increase from baseline in serum bactericidal antibody, for each serogroup. Evidence for clinical efficacy against serogroup specific meningococcal disease in school-age children and adults has been obtained from historical field trials and observational studies with other high molecular weight polysaccharide vaccines containing meningococcal serogroup A and/or C components. (6) No studies have been conducted to evaluate the efficacy of meningococcal polysaccharide vaccines against disease due to serogroups Y and W-135.

Menomune – A/C/Y/W-135 vaccine was used as the control vaccine in three US, multi-center, clinical trials designed primarily to evaluate the immunogenicity and safety of Menactra vaccine in children (2–10 years old), adolescents (11–18 years old), and adults (18–55 years old), respectively. In these trials, participants in the control arm received a dose of Menomune–A/C/Y/W-135 vaccine. Sera were obtained before and approximately 28 days after vaccination.

The Serum Bactericidal Assay (SBA) used to test sera contained an exogenous complement source that was either human (SBA-H) or, when correlated to SBA-H, baby rabbit (SBA-BR). (13)

Data on immune responses, as measured by SBA-H, following Menomune–A/C/Y/W-135 vaccine in a subset of children 2–10 years old are presented in Table 3. Data on immune responses, as measured by SBA-BR, following Menomune–A/C/Y/W-135 vaccine in adolescents and adults are presented in Table 4.

Table 3: Bactericidal Antibody Responses* to Menomune-A/C/Y/W-135 vaccine 28 Days After Vaccination for Subsets of Participants Aged 2-3 and 4-10 Years

Menomune-A/C/Y/W-135 vaccine Aged 2-3 Years N†=50-53				Menomune–A/C/Y/W-135 vaccine Aged 4-10 Years N†=84
Serogroup			(95% CI) ‡	Serogroup			(95% CI) ‡
The study was designed to show the safety and immunogenicity of Menactra vaccine are non-inferior to that of Menomune–A/C/Y/W-135 vaccine. The table shows the immune response in Menomune–A/C/Y/W-135 vaccine participants from this study.
* Serum Bactericidal Assay with an exogenous human complement (SBA-H) source. † N = Number of subset participants with at least one valid serology result at Day 0 and Day 28. ‡ The 95% CI for the Geometric Mean Titer (GMT) was calculated based on an approximation to the normal distribution.
A	% ≥ 1:8	64	50,77	A	% ≥ 1:8	55	44,66
	GMT	10	7,12		GMT	7	6,9
C	% ≥ 1:8	38	25,53	C	% ≥ 1:8	48	37,59
	GMT	11	5,21		GMT	12	7,18
Y	% ≥ 1:8	73	59,84	Y	% ≥ 1:8	92	84,97
	GMT	18	11,27		GMT	46	33,66
W-135	% ≥ 1:8	33	20,47	W-135	% ≥ 1:8	79	68,87
	GMT	5	3,6		GMT	20	14,27

In participants 2-3 years of age with undetectable pre-vaccination SBA titers (ie, <4 at Day 0), rates of seroconversion (defined as SBA titer ≥8 at Day 28) following Menomune-A/C/Y/W-135 vaccine were 55%, serogroup A (n=16/29); 30%, serogroup C (n=13/43); 57%, serogroup Y (n=17/30); 26%, serogroup W-135 (n=11/43).

In participants 4-10 years of age with undetectable pre-vaccination SBA titers (ie, <4 at Day 0), rates of seroconversion (defined as SBA titer ≥8 at Day 28) following Menomune–A/C/Y/W-135 vaccine were 48%, serogroup A (n=10/21); 38%, serogroup C (n=19/50); 84%, serogroup Y (n=38/45); 68%, serogroup W-135 (n=26/38).

Table 4: Bactericidal Antibody Responses* to Menomune – A/C/Y/W-135 Vaccine 28 Days After Vaccination for Participants Aged 11-18 and 18-55 Years

Menomune–A/C/Y/W-135 vaccine Aged 11-18 Years N†=423				Menomune–A/C/Y/W-135 vaccine Aged 18-55 Years N†=1098
Both studies (11-18 and 18-55 years of age) were designed to show the safety and immunogenicity of Menactra vaccine are non-inferior to that of Menomune–A/C/Y/W-135 vaccine. The table shows the immune response in Menomune–A/C/Y/W-135 vaccine participants from these studies.
* Serum Bactericidal Assay with baby rabbit complement (SBA-BR). † N = Number of participants with valid serology results at Day 0 and Day 28. ‡ The 95% CI for the GMT was calculated based on an approximation to the normal distribution. § The proportion of subjects with a ≥ 4-fold rise from baseline in SBA-BR titer for N. meningitidis for each of the serogroups A, C, Y and W-135, 28 days following vaccination with Menomune–A/C/Y/W-135 vaccine.
Serogroup			(95% CI) ‡	Serogroup			(95% CI) ‡
A	% ≥4-fold rise§	92.4	(89.5, 94.8)	A	% ≥4-fold rise§	84.6	(82.3, 86.7)
	GMT	3246	(2910, 3620)		GMT	4114	(3832, 4417)
C	% ≥4-fold rise§	88.7	(85.2, 91.5)	C	% ≥4-fold rise§	89.7	(87.8, 91.4)
	GMT	1639	(1406, 1911)		GMT	3469	(3148, 3823)
Y	% ≥4-fold rise§	80.1	(76.0, 83.8)	Y	% ≥4-fold rise§	79.4	(76.9, 81.8)
	GMT	1228	(1088, 1386)		GMT	2449	(2237, 2680)
W-135	% ≥4-fold rise§	95.3	(92.8, 97.1)	W-135	% ≥4-fold rise§	94.4	(92.8, 95.6)
	GMT	1545	(1384, 1725)		GMT	1871	(1723, 2032)

In participants 11-18 years of age with undetectable pre-vaccination SBA titers (ie, <8 at Day 0), rates of seroconversion (defined as a ≥ 4-fold rise in Day 28 SBA titers) following Menomune-A/C/Y/W-135 vaccine were 100%, serogroup A (n=93/93); 99%, serogroup C (n=151/152); 100%, serogroup Y (n=47/47); 99%, serogroup W-135 (n=138/139).

In participants 18-55 years of age with undetectable pre-vaccination SBA titers (ie, <8 at Day 0), rates of seroconversion (defined as a ≥ 4-fold rise in Day 28 SBA titers) following Menomune-A/C/Y/W-135 vaccine were 99%, serogroup A (n=143/144); 98%, serogroup C (n=297/304); 97%, serogroup Y (n=221/228); 99%, serogroup W-135 (n=325/328).

15. REFERENCES

1

Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54 (No. RR - 7): 1-21.

2

Centers for Disease Control and Prevention. Revised recommendations of the Advisory Committee on Immunization Practices to vaccinate all persons aged 11-18 years with meningococcal conjugate vaccine. MMWR 2007;56:794-5.

3

Centers for Disease Control and Prevention. Recommendation from the Advisory Committee on Immunization Practices (ACIP) for use of quadrivalent meningococcal conjugate vaccine (MCV4) in children aged 2-10 years at increased risk for invasive meningococcal disease. MMWR 2007;56:1265-6.

4

Recommendations of the Advisory Committee on Immunization Practices (ACIP) General Recommendations on Immunization. MMWR 2006 December 01;55(RR15):1-48.

5

Reingold AL, et al. Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine. Lancet. 1985;No.8447:114-118.

6

Granoff DM, et al. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: WB Saunders Company; 2008:399-434.

7

Mueller H, et al. A protein-free medium for primary isolation of the gonococcus and meningococcus. Proc Soc Exp Biol Med 1941;48:330.

8

Watson RG, et al. The specific hapten of group C (group II a) meningococcus. II. Chemical nature. J Immunol. 1958;81:337.

9

Tiesjema RH, et al. Enhanced stability of meningococcal polysaccharide vaccines by using lactose as a menstruum for lyophilization. Bull WHO 1977;55:43-48.

10

WHO Technical Report Series, 1981;No.658.

11

Mäkelä PH, et al. Evolution of conjugate vaccines. Expert Rev Vaccines 2002;1(3):399-410.

12

Goldschneider I, et al. Human immunity to the meningococcus. I. The Role of Humoral Antibodies. J Exp Med 1969;129:1307-1326.

13

Maslanka SE, et al. Standardization and a Multilaboratory Comparison of Neisseria meningitidis Serogroup A and C Serum Bactericidal Assays. Clin and Diag Lab Immunol 1997;156-167.

16. HOW SUPPLIED/STORAGE AND HANDLING

. How Supplied

One single dose vial of lyophilized vaccine, with one 0.6 mL vial of diluent (contains no preservative). NDC 49281-489-01.

One 10 dose vial of lyophilized vaccine, with one 6.0 mL vial of diluent (contains preservative). NDC 49281-489-91.

. Storage

Store lyophilized vaccine, diluent, and reconstituted vaccine, when not in use, at 2° to 8°C (35° to 46°F). Do not freeze.

Do not use after the expiration date shown on the vial labels of the lyophilized vaccine and diluent.

Discard remainder of reconstituted vaccine from multidose vials within 35 days after reconstitution. Vaccine from single dose vials should be used immediately after reconstitution.

17. PATIENT COUNSELING INFORMATION

Before administration of Menomune – A/C/Y/W-135 vaccine, health-care providers should inform the patient, parent or guardian of the benefits and risks of the vaccine. The health-care provider should provide the Vaccine Information Statements which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. Patients, parents, or guardians should be instructed to report adverse reactions to their health-care provider.

Rx only

Product information

as of January 2009

Manufactured by:

Sanofi Pasteur Inc.

Swiftwater PA 18370 USA

5484

PRINCIPAL DISPLAY PANEL

NDC 49281-489-91

10 Doses

Meningococcal

Polysaccharide

Vaccine, Groups A,

C, Y and W-135

Combined

Rx only

Menomune® – A/C/Y/W-135

sanofi pasteur

Menomune - A/C/Y/W-135 COMBINED  neisseria meningitidis group a polysaccharide antigen, a, neisseria meningitidis group c polysaccharide antigen, a, neisseria meningitidis group y polysaccharide antigen, a and neisseria meningitidis group w-135 polysaccharide antigen, a  kit

Mens Kirkland Minoxidil Extra Strength

Generic Name: minoxidil

Dosage Form: topical solution
Men's Kirkland Extra Strength 5%

Unscented Solution

Carton

Drug Facts

Active ingredient

Minoxidil 5% w/v

Purpose

Hair regrowth treatment for men

Use

to regrow hair on the top of the scalp (vertex only, see pictures on side of carton)

Warnings

For external use only. For use by men only.

Flammable: Keep away from fire or flame

Do not use if

• you are a woman


• your amount of hair loss is different than that shown on the side of this carton or your hair loss is on the front of the scalp. 5% minoxidil topical solution is not intended for frontal baldness or receding hairline.


• you have no family history of hair loss


• your hair loss is sudden and/or patchy


• you do not know the reason for your hair loss


• you are under 18 years of age. Do not use on babies and children.


• your scalp is red, inflamed, infected, irritated, or painful


• you use other medicines on the scalp

Ask a doctor before use if you have heart disease

When using this product

• do not apply on other parts of the body


• avoid contact with the eyes. In case of accidental contact, rinse eyes with large amounts of cool tap water.


• some people have experienced changes in hair color and/or texture


• it takes time to regrow hair. Results may occur at 2 months with twice a day usage. For some men, you may need to use this product for at least 4 months before you see results.


• the amount of hair regrowth is different for each person. This product will not work for all men.

Stop use and ask a doctor if

• chest pain, rapid heartbeat, faintness, or dizziness occurs


• sudden, unexplained weight gain occurs


• your hands or feet swell


• scalp irritation or redness occurs


• unwanted facial hair growth occurs


• you do not see hair regrowth in 4 months

May be harmful if used when pregnant or breast-feeding.

Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away.

Directions

• apply one mL with dropper 2 times a day directly onto the scalp in the hair loss area


• using more or more often will not improve results


• continued use is necessary to increase and keep your hair regrowth, or hair loss will begin again

Other information

• see hair loss pictures on side of this carton


• before use, read all information on carton and enclosed booklet


• keep the carton. It contains important information.


• hair regrowth has not been shown to last longer than 48 weeks in large clinical trials with continuous treatment with 5% minoxidil topical solution for men


• in clinical studies with mostly white men aged 18-49 years with moderate degrees of hair loss, 5% minoxidil topical solution for men provided more hair regrowth than 2% minoxidil topical solution


• store at controlled room temperature 20° to 25° C (68° to 77° F)

Inactive ingredients

alcohol, propylene glycol, purified water

Questions?

• call us at 1-877-907-6424

PRINCIPAL DISPLAY PANEL - 60 mL Bottle Carton

KIRKLAND

Signature™

MINOXIDIL

EXTRA STRENGTH FOR MEN

5% MINOXIDIL TOPICAL SOLUTION

HAIR REGROWTH

TREATMENT

Regrows

more hair than

2% Minoxidil

Topical Solution

Results may occur at 2 months

NOT FOR USE BY WOMEN

Unscented

3-60 mL (2 fl oz) Bottles

MENS KIRKLAND   EXTRA STRENGTH minoxidil  solution

Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 63981-111 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Minoxidil (Minoxidil) Minoxidil 50 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength alcohol   propylene glycol   water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 63981-111-01 12 PACKAGE In 1 TRAY contains a PACKAGE, COMBINATION 1 2 CARTON In 1 PACKAGE, COMBINATION This package is contained within the TRAY (63981-111-01) and contains a CARTON 1 3 BOTTLE In 1 CARTON This package is contained within the PACKAGE, COMBINATION and contains a BOTTLE, PLASTIC 1 60 mL In 1 BOTTLE, PLASTIC This package is contained within a CARTON and a PACKAGE, COMBINATION and a TRAY (63981-111-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020834	07/16/2010

Labeler - Costco Wholesale Corporation (103391843)

Revised: 08/2010Costco Wholesale Corporation

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• Alopecia

Metoject 50 mg / ml solution for injection

1. Name Of The Medicinal Product

Metoject 50 mg/ml solution for injection

2. Qualitative And Quantitative Composition

1 ml of solution contains 50 mg methotrexate (as methotrexate disodium).

1 pre-filled syringe of 0.15 ml contains 7.5 mg methotrexate.

1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate. .

1 pre-filled syringe of 0.25 ml contains 12.5 mg methotrexate.

1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate.

1 pre-filled syringe of 0.35 ml contains 17.5 mg methotrexate.

1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate.

1 pre-filled syringe of 0.45 ml contains 22.5 mg methotrexate.

1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate.

1 pre-filled syringe of 0.55 ml contains 27.5 mg methotrexate.

1 pre-filled syringe of 0.60 ml contains 30 mg methotrexate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection, in pre-filled syringe.

Clear, yellow-brown solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Metoject 50 mg/ml is indicated for the treatment of

− active rheumatoid arthritis in adult patients,

− polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

− severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients.

4.2 Posology And Method Of Administration

Metoject 50 mg/ml should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal product and its mode of action. Metoject 50 mg/ml is injected once weekly.

The patient is to be explicitly informed about the unusual fact of administration once weekly. It is advisable to determine a fixed, appropriate weekday as day of injection.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Dosage in adult patients with rheumatoid arthritis:

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. Depending on the individual activity of the disease and tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4 – 8 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis

The recommended dose is 10-15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m² body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is increased.

Due to limited data availability about intravenous use in children and adolescents, parenteral administration is limited to subcutaneous and intramuscular injection.

Patients with JIA should always be referred to a rheumatology specialist in the treatment of children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population. (see section 4.4)

Dosage in patients with psoriasis vulgaris and psoriatic arthritis:

It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can generally be expected after approximately 2 – 6 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Patients with renal impairment:

Metoject 50 mg/ml should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

Creatinine clearance (ml/min)	Dose
> 50	100 %
20 – 50	50 %
< 20	Metoject 50 mg/ml must not be used

See section 4.3

The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Patients with hepatic impairment:

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. If bilirubin is > 5 mg/dl (85.5 µmol/l), methotrexate is contraindicated.

For a full list of contraindications, see section 4.3.

Use in elderly patients:

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Use in patient with a third distribution space (pleural effusions, ascitis):

As the half-life of Methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see section 5.2 and 4.4).

Duration and method of administration:

The medicine is for single use only.

Metoject 50 mg/ml solution for injection can be given by intramuscular, intravenous or subcutaneous route (in children and adolescents only subcutaneous or intramuscular).

The overall duration of the treatment is decided by the physician.

Note:

If changing from oral to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration.

Folic acid supplementation may be considered according to current treatment guidelines.

4.3 Contraindications

Metoject 50 mg/ml is contraindicated in the case of

− hypersensitivity to methotrexate or to any of the excipients,

− liver insufficiency (see section 4.2),

− alcohol abuse,

− severe renal insufficiency (creatinine clearance less than 20 ml/min., see section 4.2 and section 4.4),

− pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia,

− serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,

− ulcers of the oral cavity and known active gastrointestinal ulcer disease,

− pregnancy, breast-feeding (see section 4.6),

− concurrent vaccination with live vaccines.

4.4 Special Warnings And Precautions For Use

Patients must be clearly informed that the therapy has to be applicated once a week, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Therefore methotrexate should be only administered by, or under the supervision of physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the recommended safety measures.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population (see section 4.2).

Recommended examinations and safety measures

Before beginning or reinstituting methotrexate therapy after a rest period:

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (at least once a month during the first six months and every three months thereafter):

An increased monitoring frequency should be considered also when the dose is increased.

1. Examination of the mouth and throat for mucosal changes

2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g. leflunomide) should be monitored closely with blood count and platelets.

3. Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications.

For psoriasis patients the need for a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and differentiate between patients with no risk factors and patients with risk factors such as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to hepatotoxic drugs or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 – 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

4. Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2 and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal insufficiency, which may result in severe undesirable effects.

Where renal function may be compromised (e.g. in the elderly), monitoring should take place more frequently. This applies in particular, when medicinal products are administered concomitantly, which affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory medicinal products) or which can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.

5. Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X

6. Methotrexate may, due to its effect on the immune system, impair the response to vaccination results and affect the result of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of eventual activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium

The absence of pregnancy should be confirmed before Metoject 50 mg/ml is administered. Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. These effects appear to be reversible on discontinuing therapy. Effective contraception in men and women should be performed during treatment and for at least six months thereafter. The possible risks of effects on reproduction should be discussed with patients of childbearing potential and their partners should be advised appropriately (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products

The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4). Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of hepatotoxicity.

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding

Methotrexate is plasma protein bound and may be displaced by other protein bound drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and non steroidal anti-inflammatory medicinal products or salicylates are combined.

Medicinal products with adverse reactions on the bone marrow

In the case of medication with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject 50 mg/ml is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulphasalazine, azathioprine, ciclosporin).

Sulphasalazine

Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulphasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Caffeine- or theophylline-containing beverages

An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft drinks, black tea) should be avoided during methotrexate therapy.

4.6 Pregnancy And Lactation

Metoject 50 mg/ml is contraindicated during pregnancy (see section 4.3). In animal studies, methotrexate has shown reproductive toxicity (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death and/or congenital abnormalities. Exposure of a limited number of pregnant women (42) resulted in an increased incidence (1:14) of malformations (cranial, cardiovascular and extremital). If methotrexate is discontinued prior to conception, normal pregnancies have been reported. Women must not get pregnant during methotrexate therapy. In case of women getting pregnant during therapy medical counselling about the risk of adverse reactions for the child associated with methotrexate therapy should be sought. Therefore, patients of a sexually mature age (women and men) must use effective contraception during treatment with Metoject 50 mg/ml and at least 6 months thereafter (see section 4.4).

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. pregnancy test, prior to initiating therapy.

As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible, already prior to therapy, and men should seek advice about the possibility of sperm preservation before starting therapy.

Lactation: Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and accordingly, breast-feeding should be discontinued prior to and throughout administration.

4.7 Effects On Ability To Drive And Use Machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject 50 mg/ml has minor or moderate influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.

The following headings are used to organise the undesirable effects in order of frequency:

Very common (

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite.

Common: Oral ulcers, diarrhoea.

Uncommon: Pharyngitis, enteritis, vomiting.

Rare: Gastrointestinal ulcers.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Skin and subcutaneous tissue disorders

Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, ecchymosis.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

General disorders and administration site conditions

Rare: Allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis, infection, sepsis, wound-healing impairment, hypogammaglobulinaemia.

Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration.

Metabolism and nutrition disorders

Uncommon: Precipitation of diabetes mellitus.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness, confusion, depression.

Very rare: Impaired vision, pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), convulsions, meningism, paralysis.

Eye disorders

Rare: Visual disturbances.

Very rare: Retinopathy.

Hepatobiliary disorders (see section 4.4)

Very common: Elevated transaminases.

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of breath and fever.

Rare: Pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of breath and bronchial asthma, pleural effusion.

Blood and lymphatic system disorders

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression.

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Reproductive system and breast disorders

Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia, myalgia, osteoporosis.

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very rare: There have been reports of individual cases of lymphoma which subsided in a number of cases once treatment with methotrexate had been discontinued. In a recent study, it could not be established that methotrexate therapy increases the incidence of lymphomas.

The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions were observed, decreasing during therapy.

4.9 Overdose

a) Symptoms of overdosage

Toxicity of methotrexate mainly affects the haematopoietic system.

b) Treatment measures in the case of overdosage

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within one hour and dosing continued until the serum levels of methotrexate are below 10 mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Folic acid analogues

ATC code: L01BA01

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and polyarthritic forms of juvenile idiopathic arthritis.

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriasis arthritis and chronic polyarthritis, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.

5.2 Pharmacokinetic Properties

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are possible (25 – 100 %). Maximum serum concentrations are achieved after 1 – 2 hours.

Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts. The terminal half-life is on average 6 – 7 hours and demonstrates considerable variation (3 – 17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites).

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle metabolite is 7

Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus.

Approx. 5 – 20 % methotrexate and 1 – 5 % 7

In the case of renal insufficiency, elimination is delayed significantly. Impaired elimination with regard to hepatic insufficiency is not known.

5.3 Preclinical Safety Data

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium hydroxide for pH adjustment

Water for injections

6.2 Incompatibilities

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

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Nature of container:

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with attached injection needle. Plunger stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe plunger

or

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with enclosed injection needle.Plunger stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe plunger.

Pack sizes:

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 0.55 ml or 0.60 ml solution are available in packs of 1, 4, 6, 12 and 24 syringes with attached s.c. injection needle and alcohol pads.

and

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml,0.55 ml or 0.60 ml solution are available in packs of 1, 4, 6, 12 and 24 syringes with enclosed s.c. injection needle and alcohol pads.

All pack sizes are available with graduation marks.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metoject 50 mg/ml.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water.

For single use only.

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

7. Marketing Authorisation Holder

medac

Gesellschaft für klinische Spezialpräparate mbH

Fehlandtstraße 3

20354 Hamburg

Germany

8. Marketing Authorisation Number(S)

PL 11587/0046

9. Date Of First Authorisation/Renewal Of The Authorisation

21/11/2008

10. Date Of Revision Of The Text

27/10/2010