Pantoprazole 40 mg gastro-resistant tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Pantoprazole 40 mg gastro-resistant tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 40 mg pantoprazole

(as pantoprazole sodium sesquihydrate 45.16 mg)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

Elliptical, biconvex, dark yellow gastro-resistant tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and adolescents 12 years of age and above

• Reflux oesophagitis.

Adults

• Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

• Gastric and duodenal ulcer.

• Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

4.2 Posology And Method Of Administration

Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.

Recommended dose

Adults and adolescents 12 years of age and above

Reflux oesophagitis

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Adults

Eradication of H. pylori in combination with two appropriate antibiotics in H. pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination therapy should be achieved. Considerations should be given to official local guidance (e.g. national recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial agents. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori:

a) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 500 mg clarithromycin

b) twice daily one tablet Pantoprazole tablets

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

+ twice daily 250 - 500 mg clarithromycin

c) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

In combination therapy for eradication of H. pylori infection, the second Pantoprazole tablets tablet should be taken 1 hour before the evening meal. The combination therapy is implemented for 7 days in general and can be prolonged for a further 7 days to a total duration of up to two weeks. If, to ensure healing of the ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and gastric ulcers should be considered.

If combination therapy is not an option, e.g. if the patient has tested negative for H. pylori, the following dose guidelines apply for Pantoprazole tablets monotherapy:

Treatment of gastric ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of Pantoprazole tablets 40 mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.

Special populations

Children below 12 years of age

Pantoprazole tablets is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group.

Hepatic Impairment

A daily dose of 20 mg pantoprazole (1 tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment of these patients (see section 4.4).

Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment for these patients.

Elderly

No dose adjustment is necessary in elderly patients.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients

4.4 Special Warnings And Precautions For Use

Hepatic Impairment

In patients with severe liver impairment, particularly those on long-term use, liver enzymes should be monitored regularly during treatment with pantoprazole. In the case of a rise in liver enzymes, pantoprazole 40mg gastro-resistant tablets should be discontinued.

Combination therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with atazanavir

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended in combination with an increase in the dose of atazanavir to 400mg with 100mg of ritonavir. A pantoprazole dose of 20mg per day should not be exceeded.

Influence on vitamin B12 absorption

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

Long term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Gastrointestinal infections caused by bacteria

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

To date, there has been no experience with treatment in children.

Note:

Prior to treatment of gastric ulcer, the possibility of malignancy should be excluded as treatment with pantoprazole 40mg gastro-resistant tablets may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of pantoprazole on the absorption of other medicinal products

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended (see section 4.4).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants, monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Lactation

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with pantoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of pantoprazole therapy to women.

4.7 Effects On Ability To Drive And Use Machines

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

4.8 Undesirable Effects

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1 % of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:

very common (

common (

uncommon (

rare (

very rare (<1/10,000),

not known (cannot be estimated from the available data).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse

Reaction frequency and therefore they are mentioned with a “not known” frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency Organ system	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system			Thrombocytopenia Leukopenia;
Immune system disorders		Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutritional disorders		Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia
Psychiatric disorders	Sleep disorders	Depression (and all aggravations)	Disorientation (and all aggravations)	Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders	Headache; Dizziness
Eye disorders		Disturbances in vison/ blurred vision
Gastrointestinal Disorders	Diarrhoea; Nausea /vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort Flatulence
Hepatobiliary disorders	Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Skin and subcutaneous tissue disorders	Rash / exanthema / eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity
Musculoskeletal, connective tissue disorders		Arthralgia; Myalgia
Renal and urinary disorders				Interstitial nephritis
Reproductive system and breast disorders		Gynaecomastia
General disorders and administration site conditions	Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up to 240mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during longterm treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

5.2 Pharmacokinetic Properties

General pharmacokinetics

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 μg/ml are achieved, and these values remain constant after multiple administration.

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

The absolute bioavailability from the tablet was found to be about 77 %. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Distribution

Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg

Elimination

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80 %) for the metabolites of pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects

Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole.

No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed halflife (2 - 3 h), excretion is still rapid and thus accumulation does not occur.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects.

A slight increase in AUC and C_max in elderly volunteers compared with younger counterparts is also not clinically relevant.

Children

Following administration of single oral doses of 20 or 40 mg pantoprazole to children aged 5 - 16 years AUC and C_max were in the range of corresponding values in adults.

Following administration of single i.v. doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 - 16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent studies an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg.

Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Sodium carbonate anhydrous

Sodium starch glycolate, Type A

Methacrylic acid copolymer

Calcium stearate

Opadry white OY-D-7233 (hypromellose, titanium dioxide, talc, macrogol, sodium lauryl sulphate)

Kollicoat MAE 30 DP yellow (methacrylic acid-ethyl acrylate copolymer dispersion 30%, propylene glycol, yellow iron oxide, titanium dioxide, talc)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Pantoprazole 40mg gastro-resistant tablets are provided in aluminium/aluminium blister packs of 2, 7, 14, 15, 28, 30, 50, 56, 60, 84, 90, 100, 112, 140, 280, 500, or 700 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0299

9. Date Of First Authorisation/Renewal Of The Authorisation

29/04/2010

10. Date Of Revision Of The Text

20.10.2011

M-M-R II Vaccine

Dosage Form: injection, powder, lyophilized, for suspension
M-M-R® II

(MEASLES, MUMPS, and RUBELLA VIRUS VACCINE LIVE)

M-M-R II Vaccine Description

M-M-R1 II (Measles, Mumps, and Rubella Virus Vaccine Live) is a live virus vaccine for vaccination against measles (rubeola), mumps, and rubella (German measles).

M-M-R II is a sterile lyophilized preparation of (1) ATTENUVAX1 (Measles Virus Vaccine Live), a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and propagated in chick embryo cell culture; (2) MUMPSVAX1 (Mumps Virus Vaccine Live), the Jeryl Lynn2 (B level) strain of mumps virus propagated in chick embryo cell culture; and (3) MERUVAX1 II (Rubella Virus Vaccine Live), the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.{1,2}

The growth medium for measles and mumps is Medium 199 (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing SPGA (sucrose, phosphate, glutamate, and recombinant human albumin) as stabilizer and neomycin.

The growth medium for rubella is Minimum Essential Medium (MEM) [a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum] containing recombinant human albumin and neomycin. Sorbitol and hydrolyzed gelatin stabilizer are added to the individual virus harvests.

The cells, virus pools, and fetal bovine serum are all screened for the absence of adventitious agents.

The reconstituted vaccine is for subcutaneous administration. Each 0.5 mL dose contains not less than 1,000 TCID50 (tissue culture infectious doses) of measles virus; 12,500 TCID50 of mumps virus; and 1,000 TCID50 of rubella virus. Each dose of the vaccine is calculated to contain sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), recombinant human albumin (≤0.3 mg), fetal bovine serum (<1 ppm), other buffer and media ingredients and approximately 25 mcg of neomycin. The product contains no preservative.

Before reconstitution, the lyophilized vaccine is a light yellow compact crystalline plug. M-M-R II, when reconstituted as directed, is clear yellow.

1

Registered trademark of MERCK & CO., Inc.

COPYRIGHT © 2009 MERCK & CO., Inc.

All rights reserved

2

Trademark of MERCK & CO., Inc.

M-M-R II Vaccine - Clinical Pharmacology

Measles, mumps, and rubella are three common childhood diseases, caused by measles virus, mumps virus (paramyxoviruses), and rubella virus (togavirus), respectively, that may be associated with serious complications and/or death. For example, pneumonia and encephalitis are caused by measles. Mumps is associated with aseptic meningitis, deafness and orchitis; and rubella during pregnancy may cause congenital rubella syndrome in the infants of infected mothers.

The impact of measles, mumps, and rubella vaccination on the natural history of each disease in the United States can be quantified by comparing the maximum number of measles, mumps, and rubella cases reported in a given year prior to vaccine use to the number of cases of each disease reported in 1995. For measles, 894,134 cases reported in 1941 compared to 288 cases reported in 1995 resulted in a 99.97% decrease in reported cases; for mumps, 152,209 cases reported in 1968 compared to 840 cases reported in 1995 resulted in a 99.45% decrease in reported cases; and for rubella, 57,686 cases reported in 1969 compared to 200 cases reported in 1995 resulted in a 99.65% decrease.{3}

Clinical studies of 284 triple seronegative children, 11 months to 7 years of age, demonstrated that M-M-R II is highly immunogenic and generally well tolerated. In these studies, a single injection of the vaccine induced measles hemagglutination-inhibition (HI) antibodies in 95%, mumps neutralizing antibodies in 96%, and rubella HI antibodies in 99% of susceptible persons. However, a small percentage (1-5%) of vaccinees may fail to seroconvert after the primary dose (see also INDICATIONS AND USAGE, Recommended Vaccination Schedule).

A study{4} of 6-month-old and 15-month-old infants born to vaccine-immunized mothers demonstrated that, following vaccination with ATTENUVAX, 74% of the 6-month-old infants developed detectable neutralizing antibody (NT) titers while 100% of the 15-month-old infants developed NT. This rate of seroconversion is higher than that previously reported for 6-month-old infants born to naturally immune mothers tested by HI assay. When the 6-month-old infants of immunized mothers were revaccinated at 15 months, they developed antibody titers equivalent to the 15-month-old vaccinees. The lower seroconversion rate in 6-month-olds has two possible explanations: 1) Due to the limit of the detection level of the assays (NT and enzyme immunoassay [EIA]), the presence of trace amounts of undetectable maternal antibody might interfere with the seroconversion of infants; or 2) The immune system of 6-month-olds is not always capable of mounting a response to measles vaccine as measured by the two antibody assays.

There is some evidence to suggest that infants who are born to mothers who had wild-type measles and who are vaccinated at less than one year of age may not develop sustained antibody levels when later revaccinated. The advantage of early protection must be weighed against the chance for failure to respond adequately on reimmunization.{5,6}

Efficacy of measles, mumps, and rubella vaccines was established in a series of double-blind controlled field trials which demonstrated a high degree of protective efficacy afforded by the individual vaccine components.{7-12} These studies also established that seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases.{13-15}

Following vaccination, antibodies associated with protection can be measured by neutralization assays, HI, or ELISA (enzyme linked immunosorbent assay) tests. Neutralizing and ELISA antibodies to measles, mumps, and rubella viruses are still detectable in most individuals 11 to 13 years after primary vaccination.{16-18} See INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females, for Rubella Susceptibility Testing.

The RA 27/3 rubella strain in M-M-R II elicits higher immediate post-vaccination HI, complement-fixing and neutralizing antibody levels than other strains of rubella vaccine{19-25} and has been shown to induce a broader profile of circulating antibodies including anti-theta and anti-iota precipitating antibodies.{26,27} The RA 27/3 rubella strain immunologically simulates natural infection more closely than other rubella vaccine viruses.{27-29} The increased levels and broader profile of antibodies produced by RA 27/3 strain rubella virus vaccine appear to correlate with greater resistance to subclinical reinfection with the wild virus,{27,29-31} and provide greater confidence for lasting immunity.

Indications and Usage for M-M-R II Vaccine

Recommended Vaccination Schedule

M-M-R II is indicated for simultaneous vaccination against measles, mumps, and rubella in individuals 12 months of age or older.

Individuals first vaccinated at 12 months of age or older should be revaccinated prior to elementary school entry. Revaccination is intended to seroconvert those who do not respond to the first dose. The Advisory Committee on Immunization Practices (ACIP) recommends administration of the first dose of M-M-R II at 12 to 15 months of age and administration of the second dose of M-M-R II at 4 to 6 years of age.{59} In addition, some public health jurisdictions mandate the age for revaccination. Consult the complete text of applicable guidelines regarding routine revaccination including that of high-risk adult populations.

Measles Outbreak Schedule

Infants Between 6 to 12 Months of Age

Local health authorities may recommend measles vaccination of infants between 6 to 12 months of age in outbreak situations. This population may fail to respond to the components of the vaccine. Safety and effectiveness of mumps and rubella vaccine in infants less than 12 months of age have not been established. The younger the infant, the lower the likelihood of seroconversion (see CLINICAL PHARMACOLOGY). Such infants should receive a second dose of M-M-R II between 12 to 15 months of age followed by revaccination at elementary school entry.{59}

Unnecessary doses of a vaccine are best avoided by ensuring that written documentation of vaccination is preserved and a copy given to each vaccinee's parent or guardian.

Other Vaccination Considerations

Non-Pregnant Adolescent and Adult Females

Immunization of susceptible non-pregnant adolescent and adult females of childbearing age with live attenuated rubella virus vaccine is indicated if certain precautions are observed (see below and PRECAUTIONS). Vaccinating susceptible postpubertal females confers individual protection against subsequently acquiring rubella infection during pregnancy, which in turn prevents infection of the fetus and consequent congenital rubella injury.{33}

Women of childbearing age should be advised not to become pregnant for 3 months after vaccination and should be informed of the reasons for this precaution.

The ACIP has stated "If it is practical and if reliable laboratory services are available, women of childbearing age who are potential candidates for vaccination can have serologic tests to determine susceptibility to rubella. However, with the exception of premarital and prenatal screening, routinely performing serologic tests for all women of childbearing age to determine susceptibility (so that vaccine is given only to proven susceptible women) can be effective but is expensive. Also, 2 visits to the health-care provider would be necessary — one for screening and one for vaccination. Accordingly, rubella vaccination of a woman who is not known to be pregnant and has no history of vaccination is justifiable without serologic testing — and may be preferable, particularly when costs of serology are high and follow-up of identified susceptible women for vaccination is not assured."{33}

Postpubertal females should be informed of the frequent occurrence of generally self-limited arthralgia and/or arthritis beginning 2 to 4 weeks after vaccination (see ADVERSE REACTIONS).

Postpartum Women

It has been found convenient in many instances to vaccinate rubella-susceptible women in the immediate postpartum period (see PRECAUTIONS, Nursing Mothers).

Other Populations

Previously unvaccinated children older than 12 months who are in contact with susceptible pregnant women should receive live attenuated rubella vaccine (such as that contained in monovalent rubella vaccine or in M-M-R II) to reduce the risk of exposure of the pregnant woman.

Individuals planning travel outside the United States, if not immune, can acquire measles, mumps, or rubella and import these diseases into the United States. Therefore, prior to international travel, individuals known to be susceptible to one or more of these diseases can either receive the indicated monovalent vaccine (measles, mumps, or rubella), or a combination vaccine as appropriate. However, M-M-R II is preferred for persons likely to be susceptible to mumps and rubella; and if monovalent measles vaccine is not readily available, travelers should receive M-M-R II regardless of their immune status to mumps or rubella.{34-36}

Vaccination is recommended for susceptible individuals in high-risk groups such as college students, health-care workers, and military personnel.{33,34,37}

According to ACIP recommendations, most persons born in 1956 or earlier are likely to have been infected with measles naturally and generally need not be considered susceptible. All children, adolescents, and adults born after 1956 are considered susceptible and should be vaccinated, if there are no contraindications. This includes persons who may be immune to measles but who lack adequate documentation of immunity such as: (1) physician-diagnosed measles, (2) laboratory evidence of measles immunity, or (3) adequate immunization with live measles vaccine on or after the first birthday.{34}

The ACIP recommends that "Persons vaccinated with inactivated vaccine followed within 3 months by live vaccine should be revaccinated with two doses of live vaccine. Revaccination is particularly important when the risk of exposure to wild-type measles virus is increased, as may occur during international travel."{34}

Post-Exposure Vaccination

Vaccination of individuals exposed to wild-type measles may provide some protection if the vaccine can be administered within 72 hours of exposure. If, however, vaccine is given a few days before exposure, substantial protection may be afforded.{34,38,39} There is no conclusive evidence that vaccination of individuals recently exposed to wild-type mumps or wild-type rubella will provide protection.{33,37}

Use With Other Vaccines

See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.

Contraindications

Hypersensitivity to any component of the vaccine, including gelatin.{40}

Do not give M-M-R II to pregnant females; the possible effects of the vaccine on fetal development are unknown at this time. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for three months following vaccination (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females and PRECAUTIONS, Pregnancy).

Anaphylactic or anaphylactoid reactions to neomycin (each dose of reconstituted vaccine contains approximately 25 mcg of neomycin).

Febrile respiratory illness or other active febrile infection. However, the ACIP has recommended that all vaccines can be administered to persons with minor illnesses such as diarrhea, mild upper respiratory infection with or without low-grade fever, or other low-grade febrile illness.{41}

Patients receiving immunosuppressive therapy. This contraindication does not apply to patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

Individuals with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems.

Primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manifestations of infection with human immunodeficiency viruses;{41-43} cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states. Measles inclusion body encephalitis{60} (MIBE), pneumonitis{61} and death as a direct consequence of disseminated measles vaccine virus infection have been reported in immunocompromised individuals inadvertently vaccinated with measles-containing vaccine.

Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated.

Warnings

Due caution should be employed in administration of M-M-R II to persons with a history of cerebral injury, individual or family histories of convulsions, or any other condition in which stress due to fever should be avoided. The physician should be alert to the temperature elevation which may occur following vaccination (see ADVERSE REACTIONS).

Hypersensitivity to Eggs

Live measles vaccine and live mumps vaccine are produced in chick embryo cell culture. Persons with a history of anaphylactic, anaphylactoid, or other immediate reactions (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) subsequent to egg ingestion may be at an enhanced risk of immediate-type hypersensitivity reactions after receiving vaccines containing traces of chick embryo antigen. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases. Such individuals may be vaccinated with extreme caution, having adequate treatment on hand should a reaction occur (see PRECAUTIONS).{45}

However, the AAP has stated, "Most children with a history of anaphylactic reactions to eggs have no untoward reactions to measles or MMR vaccine. Persons are not at increased risk if they have egg allergies that are not anaphylactic, and they should be vaccinated in the usual manner. In addition, skin testing of egg-allergic children with vaccine has not been predictive of which children will have an immediate hypersensitivity reaction...Persons with allergies to chickens or chicken feathers are not at increased risk of reaction to the vaccine."{44}

Hypersensitivity to Neomycin

The AAP states, "Persons who have experienced anaphylactic reactions to topically or systemically administered neomycin should not receive measles vaccine. Most often, however, neomycin allergy manifests as a contact dermatitis, which is a delayed-type (cell-mediated) immune response rather than anaphylaxis. In such persons, an adverse reaction to neomycin in the vaccine would be an erythematous, pruritic nodule or papule, 48 to 96 hours after vaccination. A history of contact dermatitis to neomycin is not a contraindication to receiving measles vaccine."{44}

Thrombocytopenia

Individuals with current thrombocytopenia may develop more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia with the first dose of M-M-R II (or its component vaccines) may develop thrombocytopenia with repeat doses. Serologic status may be evaluated to determine whether or not additional doses of vaccine are needed. The potential risk to benefit ratio should be carefully evaluated before considering vaccination in such cases (see ADVERSE REACTIONS).

Precautions

General

Adequate treatment provisions including epinephrine injection (1:1000), should be available for immediate use should an anaphylactic or anaphylactoid reaction occur.

Special care should be taken to ensure that the injection does not enter a blood vessel.

Children and young adults who are known to be infected with human immunodeficiency viruses and are not immunosuppressed may be vaccinated. However, vaccinees who are infected with HIV should be monitored closely for vaccine-preventable diseases because immunization may be less effective than for uninfected persons (see CONTRAINDICATIONS).{42,43}

Vaccination should be deferred for 3 months or longer following blood or plasma transfusions, or administration of immune globulin (human).{44}

Excretion of small amounts of the live attenuated rubella virus from the nose or throat has occurred in the majority of susceptible individuals 7 to 28 days after vaccination. There is no confirmed evidence to indicate that such virus is transmitted to susceptible persons who are in contact with the vaccinated individuals. Consequently, transmission through close personal contact, while accepted as a theoretical possibility, is not regarded as a significant risk.{33} However, transmission of the rubella vaccine virus to infants via breast milk has been documented (see Nursing Mothers).

There are no reports of transmission of live attenuated measles or mumps viruses from vaccinees to susceptible contacts.

It has been reported that live attenuated measles, mumps and rubella virus vaccines given individually may result in a temporary depression of tuberculin skin sensitivity. Therefore, if a tuberculin test is to be done, it should be administered either before or simultaneously with M-M-R II.

Children under treatment for tuberculosis have not experienced exacerbation of the disease when immunized with live measles virus vaccine;{46} no studies have been reported to date of the effect of measles virus vaccines on untreated tuberculous children. However, individuals with active untreated tuberculosis should not be vaccinated.

As for any vaccine, vaccination with M-M-R II may not result in protection in 100% of vaccinees.

The health-care provider should determine the current health status and previous vaccination history of the vaccinee.

The health-care provider should question the patient, parent, or guardian about reactions to a previous dose of M-M-R II or other measles-, mumps-, or rubella-containing vaccines.

Information for Patients

The health-care provider should provide the vaccine information required to be given with each vaccination to the patient, parent, or guardian.

The health-care provider should inform the patient, parent, or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.

Patients, parents, or guardians should be instructed to report any serious adverse reactions to their health-care provider who in turn should report such events to the U.S. Department of Health and Human Services through the Vaccine Adverse Event Reporting System (VAERS), 1-800-822-7967.{47}

Pregnancy should be avoided for 3 months following vaccination, and patients should be informed of the reasons for this precaution (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females, CONTRAINDICATIONS, and PRECAUTIONS, Pregnancy).

Laboratory Tests

See INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females, for Rubella Susceptibility Testing, and CLINICAL PHARMACOLOGY.

Drug Interactions

See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.

Immunosuppressive Therapy

The immune status of patients about to undergo immunosuppressive therapy should be evaluated so that the physician can consider whether vaccination prior to the initiation of treatment is indicated (see CONTRAINDICATIONS and PRECAUTIONS).

The ACIP has stated that "patients with leukemia in remission who have not received chemotherapy for at least 3 months may receive live virus vaccines. Short-term (<2 weeks), low- to moderate-dose systemic corticosteroid therapy, topical steroid therapy (e.g. nasal, skin), long-term alternate-day treatment with low to moderate doses of short-acting systemic steroid, and intra-articular, bursal, or tendon injection of corticosteroids are not immunosuppressive in their usual doses and do not contraindicate the administration of [measles, mumps, or rubella vaccine]."{33,34,37}

Immune Globulin

Administration of immune globulins concurrently with M-M-R II may interfere with the expected immune response.{33,34,44}

See also PRECAUTIONS, General.

Carcinogenesis, Mutagenesis, Impairment of Fertility

M-M-R II has not been evaluated for carcinogenic or mutagenic potential, or potential to impair fertility.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with M-M-R II. It is also not known whether M-M-R II can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, the vaccine should not be administered to pregnant females; furthermore, pregnancy should be avoided for 3 months following vaccination (see INDICATIONS AND USAGE, Non-Pregnant Adolescent and Adult Females and CONTRAINDICATIONS).

In counseling women who are inadvertently vaccinated when pregnant or who become pregnant within 3 months of vaccination, the physician should be aware of the following: (1) In a 10-year survey involving over 700 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 189 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome;{48} (2) Mumps infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect the placenta and fetus, there is no evidence that it causes congenital malformations in humans;{37} and (3) Reports have indicated that contracting wild-type measles during pregnancy enhances fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent to infection with wild-type measles during pregnancy.{57,58} There are no adequate studies of the attenuated (vaccine) strain of measles virus in pregnancy. However, it would be prudent to assume that the vaccine strain of virus is also capable of inducing adverse fetal effects.

Nursing Mothers

It is not known whether measles or mumps vaccine virus is secreted in human milk. Recent studies have shown that lactating postpartum women immunized with live attenuated rubella vaccine may secrete the virus in breast milk and transmit it to breast-fed infants.{49} In the infants with serological evidence of rubella infection, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella.{50,51} Caution should be exercised when M-M-R II is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of measles vaccine in infants below the age of 6 months have not been established (see also CLINICAL PHARMACOLOGY). Safety and effectiveness of mumps and rubella vaccine in infants less than 12 months of age have not been established.

Geriatric Use

Clinical studies of M-M-R II did not include sufficient numbers of seronegative subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Adverse Reactions

The following adverse reactions are listed in decreasing order of severity, without regard to causality, within each body system category and have been reported during clinical trials, with use of the marketed vaccine, or with use of monovalent or bivalent vaccine containing measles, mumps, or rubella:

Body as a Whole

Panniculitis; atypical measles; fever; syncope; headache; dizziness; malaise; irritability.

Cardiovascular System

Vasculitis.

Digestive System

Pancreatitis; diarrhea; vomiting; parotitis; nausea.

Endocrine System

Diabetes mellitus.

Hemic and Lymphatic System

Thrombocytopenia (see WARNINGS, Thrombocytopenia); purpura; regional lymphadenopathy; leukocytosis.

Immune System

Anaphylaxis and anaphylactoid reactions have been reported as well as related phenomena such as angioneurotic edema (including peripheral or facial edema) and bronchial spasm in individuals with or without an allergic history.

Musculoskeletal System

Arthritis; arthralgia; myalgia.

Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of infection with wild-type rubella and vary in frequency and severity with age and sex, being greatest in adult females and least in prepubertal children. This type of involvement as well as myalgia and paresthesia, have also been reported following administration of MERUVAX II.

Chronic arthritis has been associated with wild-type rubella infection and has been related to persistent virus and/or viral antigen isolated from body tissues. Only rarely have vaccine recipients developed chronic joint symptoms.

Following vaccination in children, reactions in joints are uncommon and generally of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (children: 0-3%; women: 12-26%),{17,52,53} and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and in adult women. Even in women older than 35 years, these reactions are generally well tolerated and rarely interfere with normal activities.

Nervous System

Encephalitis; encephalopathy; measles inclusion body encephalitis (MIBE) (see CONTRAINDICATIONS); subacute sclerosing panencephalitis (SSPE); Guillain-Barré Syndrome (GBS); febrile convulsions; afebrile convulsions or seizures; ataxia; polyneuritis; polyneuropathy; ocular palsies; paresthesia.

Experience from more than 80 million doses of all live measles vaccines given in the U.S. through 1975 indicates that significant central nervous system reactions such as encephalitis and encephalopathy, occurring within 30 days after vaccination, have been temporally associated with measles vaccine very rarely.{54} In no case has it been shown that reactions were actually caused by vaccine. The Centers for Disease Control and Prevention has pointed out that "a certain number of cases of encephalitis may be expected to occur in a large childhood population in a defined period of time even when no vaccines are administered". However, the data suggest the possibility that some of these cases may have been caused by measles vaccines. The risk of such serious neurological disorders following live measles virus vaccine administration remains far less than that for encephalitis and encephalopathy with wild-type measles (one per two thousand reported cases).

Post-marketing surveillance of the more than 200 million doses of M-M-R and M-M-R II that have been distributed worldwide over 25 years (1971 to 1996) indicates that serious adverse events such as encephalitis and encephalopathy continue to be rarely reported.{17}

There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of infection with wild-type measles but did receive measles vaccine. Some of these cases may have resulted from unrecognized measles in the first year of life or possibly from the measles vaccination. Based on estimated nationwide measles vaccine distribution, the association of SSPE cases to measles vaccination is about one case per million vaccine doses distributed. This is far less than the association with infection with wild-type measles, 6-22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study conducted by the Centers for Disease Control and Prevention suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent higher risk of SSPE.{55}

Cases of aseptic meningitis have been reported to VAERS following measles, mumps, and rubella vaccination. Although a causal relationship between the Urabe strain of mumps vaccine and aseptic meningitis has been shown, there is no evidence to link Jeryl Lynn™ mumps vaccine to aseptic meningitis.

Respiratory System

Pneumonia; pneumonitis (see CONTRAINDICATIONS); sore throat; cough; rhinitis.

Skin

Stevens-Johnson syndrome; erythema multiforme; urticaria; rash; measles-like rash; pruritis.

Local reactions including burning/stinging at injection site; wheal and flare; redness (erythema); swelling; induration; tenderness; vesiculation at injection site.

Special Senses — Ear

Nerve deafness; otitis media.

Special Senses — Eye

Retinitis; optic neuritis; papillitis; retrobulbar neuritis; conjunctivitis.

Urogenital System

Epididymitis; orchitis.

Other

Death from various, and in some cases unknown, causes has been reported rarely following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals (see CONTRAINDICATIONS). No deaths or permanent sequelae were reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982 to 1993.{56}

Under the National Childhood Vaccine Injury Act of 1986, health-care providers and manufacturers are required to record and report certain suspected adverse events occurring within specific time periods after vaccination. However, the U.S. Department of Health and Human Services (DHHS) has established a Vaccine Adverse Event Reporting System (VAERS) which will accept all reports of suspected events.{47} A VAERS report form as well as information regarding reporting requirements can be obtained by calling VAERS 1-800-822-7967.

M-M-R II Vaccine Dosage and Administration

FOR SUBCUTANEOUS ADMINISTRATION

Do not inject intravascularly.

The dose for any age is 0.5 mL administered subcutaneously, preferably into the outer aspect of the upper arm.

The recommended age for primary vaccination is 12 to 15 months.

Revaccination with M-M-R II is recommended prior to elementary school entry. See also INDICATIONS AND USAGE, Recommended Vaccination Schedule.

Children first vaccinated when younger than 12 months of age should receive another dose between 12 to 15 months of age followed by revaccination prior to elementary school entry.{59} See also INDICATIONS AND USAGE, Measles Outbreak Schedule.

Immune Globulin (IG) is not to be given concurrently with M-M-R II (see PRECAUTIONS, General and PRECAUTIONS, Drug Interactions).

CAUTION: A sterile syringe free of preservatives, antiseptics, and detergents should be used for each injection and/or reconstitution of the vaccine because these substances may inactivate the live virus vaccine. A 25 gauge, 5/8" needle is recommended.

To reconstitute, use only the diluent supplied, since it is free of preservatives or other antiviral substances which might inactivate the vaccine.

Single Dose Vial — First withdraw the entire volume of diluent into the syringe to be used for reconstitution. Inject all the diluent in the syringe into the vial of lyophilized vaccine, and agitate to mix thoroughly. If the lyophilized vaccine cannot be dissolved, discard. Withdraw the entire contents into a syringe and inject the total volume of restored vaccine subcutaneously.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis B and other infectious agents from one person to another.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. M-M-R II, when reconstituted, is clear yellow.

Use With Other Vaccines

M-M-R II should be given one month before or after administration of other live viral vaccines.

M-M-R II has been administered concurrently with VARIVAX1 [Varicella Virus Vaccine Live (Oka/Merck)], and PedvaxHIB1 [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] using separate injection sites and syringes. No impairment of immune response to individually tested vaccine antigens was demonstrated. The type, frequency, and severity of adverse experiences observed with M-M-R II were similar to those seen when each vaccine was given alone.

Routine administration of DTP (diphtheria, tetanus, pertussis) and/or OPV (oral poliovirus vaccine) concurrently with measles, mumps and rubella vaccines is not recommended because there are limited data relating to the simultaneous administration of these antigens.

However, other schedules have been used. The ACIP has stated "Although data are limited concerning the simultaneous administration of the entire recommended vaccine series (i.e., DTaP [or DTwP], IPV [or OPV], Hib with or without Hepatitis B vaccine, and varicella vaccine), data from numerous studies have indicated no interference between routinely recommended childhood vaccines (either live, attenuated, or killed). These findings support the simultaneous use of all vaccines as recommended."{32}

How is M-M-R II Vaccine Supplied

No. 4681 — M-M-R II is supplied as follows: (1) a box of 10 single-dose vials of lyophilized vaccine (package A), NDC 0006-4681-00; and (2) a box of 10 vials of diluent (package B). To conserve refrigerator space, the diluent may be stored separately at room temperature.

Storage

To maintain potency, M-M-R II must be stored between -58°F and +46°F (-50°C to +8°C). Use of dry ice may subject M-M-R II to temperatures colder than -58°F (-50°C).

Protect the vaccine from light at all times, since such exposure may inactivate the viruses.

Before reconstitution, store the lyophilized vaccine at 36°F to 46°F (2°C to 8°C). The diluent may be stored in the refrigerator with the lyophilized vaccine or separately at room temperature. Do not freeze the diluent.

It is recommended that the vaccine be used as soon as possible after reconstitution. Store reconstituted vaccine in the vaccine vial in a dark place at 36°F to 46°F (2°C to 8°C) and discard if not used within 8 hours.

For information regarding stability under conditions other than those recommended, call 1-800-MERCK-90.

REFERENCES

1. Plotkin, S.A.; Cornfeld, D.; Ingalls, T.H.: Studies of immunization with living rubella virus: Trials in children with a strain cultured from an aborted fetus, Am. J. Dis. Child. 110: 381-389, 1965.


2. Plotkin, S.A.; Farquhar, J.; Katz, M.; Ingalls, T.H.: A new attenuated rubella virus grown in human fibroblasts: Evidence for reduced nasopharyngeal excretion, Am. J. Epidemiol. 86: 468-477, 1967.


3. Monthly Immunization Table, MMWR 45(1): 24-25, January 12, 1996.


4. Johnson, C.E.; et al: Measles Vaccine Immunogenicity in 6- Versus 15-Month-Old Infants Born to Mothers in the Measles Vaccine Era, Pediatrics, 93(6): 939-943, 1994.


5. Linneman, C.C.; et al: Measles Immunity After Vaccination: Results in Children Vaccinated Before 10 Months of Age, Pediatrics, 69(3): 332-335, March 1982.


6. Stetler, H.C.; et al: Impact of Revaccinating Children Who Initially Received Measles Vaccine Before 10 Months of Age, Pediatrics 77(4): 471-476, April 1986.


7. Hilleman, M.R.; Buynak, E.B.; Weibel, R.E.; et al: Development and Evaluation of the Moraten Measles Virus Vaccine, JAMA 206(3): 587-590, 1968.


8. Weibel, R.E.; Stokes, J.; Buynak, E.B.; et al: Live, Attenuated Mumps Virus Vaccine 3. Clinical and Serologic Aspects in a Field Evaluation, N. Engl. J. Med. 276: 245-251, 1967.


9. Hilleman, M.R.; Weibel, R.E.; Buynak, E.B.; et al: Live, Attenuated Mumps Virus Vaccine 4. Protective Efficacy as Measured in a Field Evaluation, N. Engl. J. Med. 276: 252-258, 1967.


10. Cutts, F.T.; Henderson, R.H.; Clements, C.J.; et al: Principles of measles control, Bull WHO 69(1): 1-7, 1991.


11. Weibel, R.E.; Buynak, E.B.; Stokes, J.; et al: Evaluation Of Live Attenuated Mumps Virus Vaccine, Strain Jeryl Lynn, First International Conference on Vaccines Against Viral and Rickettsial Diseases of Man, World Health Organization, No. 147, May 1967.


12. Leibhaber, H.; Ingalls, T.H.; LeBouvier, G.L.; et al: Vaccination With RA 27/3 Rubella Vaccine, Am. J. Dis. Child. 123: 133-136, February 1972.


13. Rosen, L.: Hemagglutination and Hemagglutination-Inhibition with Measles Virus, Virology 13: 139-141, January 1961.


14. Brown, G.C.; et al: Fluorescent-Antibody Marker for Vaccine-Induced Rubella Antibodies, Infection and Immunity 2(4): 360-363, 1970.


15. Buynak, E.B.; et al: Live Attenuated Mumps Virus Vaccine 1. Vaccine Development, Proceedings of the Society for Experimental Biology and Medicine, 123: 768-775, 1966.


16. Weibel, R.E.; Carlson, A.J.; Villarejos, V.M.; Buynak, E.B.; McLean, A.A.; Hilleman, M.R.: Clinical and Laboratory Studies of Combined Live Measles, Mumps, and Rubella Vaccines Using the RA 27/3 Rubella Virus, Proc. Soc. Exp. Biol. Med. 165: 323-326, 1980.


17. Unpublished data from the files of Merck Research Laboratories.


18. Watson, J.C.; Pearson, J.S.; Erdman, D.D.; et al: An Evaluation of Measles Revaccination Among School-Entry Age Children, 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract #268, 143, 1991.


19. Fogel, A.; Moshkowitz, A.; Rannon, L.; Gerichter, Ch.B.: Comparative trials of RA 27/3 and Cendehill rubella vaccines in adult and adolescent females, Am. J. Epidemiol. 93: 392-393, 1971.


20. Andzhaparidze, O.G.; Desyatskova, R.G.; Chervonski, G.I.; Pryanichnikova, L.V.: Immunogenicity and reactogenicity of live attenuated rubella virus vaccines, Am. J. Epidemiol. 91: 527-530, 1970.


21. Freestone, D.S.; Reynolds, G.M.; McKinnon, J.A.; Prydie, J.: Vaccination of schoolgirls against rubella. Assessment of serological status and a comparative trial of Wistar RA 27/3 and Cendehill strain live attenuated rubella vaccines in 13-year-old schoolgirls in Dudley, Br. J. Prev. Soc. Med. 29: 258-261, 1975.


22. Grillner, L.; Hedstrom, C.E.; Bergstrom, H.; Forssman, L.; Rigner, A.; Lycke, E.: Vaccination against rubella of newly delivered women, Scand. J. Infect. Dis. 5: 237-241, 1973.


23. Grillner, L.: Neutralizing antibodies after rubella vaccination of newly delivered women: a comparison between three vaccines, Scand. J. Infect. Dis. 7: 169-172, 1975.


24. Wallace, R.B.; Isacson, P.: Comparative trial of HPV-77, DE-5 and RA 27/3 live-attenuated rubella vaccines, Am. J. Dis. Child. 124: 536-538, 1972.


25. Lalla, M.; Vesikari, T.; Virolainen, M.: Lymphoblast proliferation and humoral antibody response after rubella vaccination, Clin. Exp. Immunol. 15: 193-202, 1973.


26. LeBouvier, G.L.; Plotkin, S.A.: Precipitin responses to rubella vaccine RA 27/3, J. Infect. Dis. 123: 220-223, 1971.


27. Horstmann, D.M.: Rubella: The challenge of its control, J. Infect. Dis. 123: 640-654, 1971.


28. Ogra, P.L.; Kerr-Grant, D.; Umana, G.; Dzierba, J.; Weintraub, D.: Antibody response in serum and nasopharynx after naturally acquired and vaccine-induced infection with rubella virus, N. Engl. J. Med. 285: 1333-1339, 1971.


29. Plotkin, S.A.; Farquhar, J.D.; Ogra, P.L.: Immunologic properties of RA 27/3 rubella virus vaccine, J. Am. Med. Assoc. 225: 585-590, 1973.


30. Liebhaber, H.; Ingalls, T.H.; LeBouvier, G.L.; Horstmann, D.M.: Vaccination with RA 27/3 rubella vaccine. Persistence of immunity and resistance to challenge after two years, Am. J. Dis. Child. 123: 133-136, 1972.


31. Farquhar, J.D.: Follow-up on rubella vaccinations and experience with subclinical reinfection, J. Pediatr. 81: 460-465, 1972.


32. Centers for Disease Control and Prevention. Recommended childhood immunization schedule — United States, January-June 1996, MMWR 44(51 & 52): 940-943, January 5, 1996.


33. Rubella Prevention: Recommendation of the Immunization Practices Advisory Committee (ACIP), MMWR 39(RR-15): 1-18, November 23, 1990.


34. Measles Prevention: Recommendations of the Immunization Practices Advisory Committee (ACIP), MMWR 38(S-9): 5-22, December 29, 1989.


35. Jong, E.C., The Travel and Tropical Medicine Manual, W.B. Saunders Company, p. 12-16, 1987.


36. Committee on Immunization Council of Medical Societies, American College of Physicians, Phila., PA, Guide for Adult Immunization, First Edition, 1985.


37. Recommendations of the Immunization Practices Advisory Committee (ACIP), Mumps Prevention, MMWR 38(22): 388-400, June 9, 1989.


38. King, G.E.; Markowitz, L.E.; Patriarca, P.A.; et al: Clinical Efficacy of Measles Vaccine During the 1990 Measles Epidemic, Pediatr. Infect. Dis. J. 10(12): 883-888, December 1991.


39. Krasinski, K.; Borkowsky, W.: Measles and Measles Immunity in Children Infected With Human Immunodeficiency Virus, JAMA 261(17): 2512-2516, 1989.


40. Kelso, J.M.; Jones, R.T.; Yunginger, J.W.: Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin, J. Allergy Clin. Immunol. 91: 867-872, 1993.


41. General Recommendations on Immunization, Recommendations of the Advisory Committee on Immunization Practices, MMWR 43(RR-1): 1-38, January 28, 1994.


42. Center for Disease Control: Immunization of Children Infected with Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus, Annals of Internal Medicine, 106: 75-78, 1987.


43. Krasinski, K.; Borkowsky, W.; Krugman, S.: Antibody following measles immunization in children infected with human T-cell lymphotropic virus-type III/lymphadenopathy associated virus (HTLV-III/LAV) [Abstract]. In: Program and abstracts of the International Conference on Acquired Immunodeficiency Syndrome, Paris, France, June 23-25, 1986.


44. Pe

insulin aspart

Generic Name: insulin aspart (IN su lin AS part)

Brand Names: NovoLOG, NovoLOG FlexPen, NovoLOG PenFill

What is insulin aspart?

Insulin is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. Insulin aspart is a fast-acting form of insulin.

Insulin aspart is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. Insulin aspart is usually given together with another long-acting insulin.

Insulin aspart may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about insulin aspart?

Insulin aspart is a fast-acting insulin that begins to work very quickly. After using it, you should eat a meal within 5 to 10 minutes.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

What should I discuss with my healthcare provider before using insulin aspart?

Do not use this medication if you are allergic to insulin, or if you are having an episode of hypoglycemia (low blood sugar).

Before using insulin aspart, tell your doctor if you have liver or kidney disease.

Tell your doctor about all other medications you use, including any oral (taken by mouth) diabetes medications.

Insulin aspart is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether insulin aspart passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use insulin aspart?

Use this medication exactly as it was prescribed for you. Do not use it in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

Insulin aspart is given as an injection (shot) under your skin, using a needle and syringe or an insulin pump. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject this medicine. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

Insulin aspart is a fast-acting medication that begins to work very quickly. After using insulin aspart, you should eat a meal within 5 to 10 minutes.

Insulin aspart should be thin, clear, and colorless. Do not use the medication if it looks cloudy, has changed colors, or has any particles in it. Call your doctor for a new prescription.

Choose a different place in your injection skin area each time you use this medication. Do not inject into the same place two times in a row.

If you use this medication with an insulin pump, do not mix or dilute insulin aspart with any other insulin. Call your doctor at once if you think your infusion pump is not working properly.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Some insulin needles can be used more than once, depending on needle brand and type. But a reused needle must be properly cleaned, recapped, and inspected for bending or breakage. Reusing needles also increases your risk of infection. Ask your doctor or pharmacist whether you are able to reuse your insulin needles.

Infusion pump tubing, catheters, and the needle location on your skin should be changed every 48 hours. Throw away any medication leftover in the reservoir.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

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

Watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Ask your doctor how to adjust your insulin aspart dose if needed. Do not change your dose without first talking to your doctor. Carry an ID card or wear a medical alert bracelet stating that you have diabetes, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are diabetic. Storing unopened vials, cartridges, or injection pens: Keep in the carton and store in a refrigerator, protected from light. Throw away any insulin not used before the expiration date on the medicine label. Unopened vials, cartridges, or injection pens may also be stored at room temperature for up to 28 days, away from heat and bright light. Throw away any insulin not used within 28 days. Storing after your first use: Keep the "in-use" vials, cartridges, or injection pens at room temperature and use within 28 days. Do not refrigerate.

Do not freeze insulin aspart, and throw away the medication if it has become frozen.

What happens if I miss a dose?

Since insulin aspart is used before meals, you may not be on a timed dosing schedule. Whenever you use insulin aspart, be sure to eat a meal within 5 to 10 minutes. Do not use extra insulin aspart to make up a missed dose.

It is important to keep insulin aspart on hand at all times. Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An insulin overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, seizure (convulsions), or coma.

What should I avoid while using insulin aspart?

Do not change the brand of insulin aspart or syringe you are using without first talking to your doctor or pharmacist. Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using insulin aspart. Do not expose insulin aspart to high heat. Throw the medication away if it becomes hotter than 98 degrees F.

Insulin aspart side effects

Get emergency medical help if you have any of these signs of insulin allergy: itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out. Call your doctor if you have a serious side effect such as:

• 
  

  swelling in your hands or feet; or

  
  


• 
  

  low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling).

  
  

Hypoglycemia, or low blood sugar, is the most common side effect of insulin aspart. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, trouble concentrating, confusion, or seizure (convulsions). Watch for signs of low blood sugar. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar.

Insulin aspart can also cause hypokalemia (low potassium levels in the blood). Call your doctor at once if you have symptoms such as dry mouth, increased thirst, increased urination, uneven heartbeats, muscle pain or weakness, leg pain or discomfort, or confusion.

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.

Insulin aspart Dosing Information

Usual Adult Dose for Diabetes Mellitus Type I:

Insulin aspart is a short acting insulin with a rapid onset and should be given immediately before meals. 50 to 70% of the daily insulin requirement may be provided by aspart and the remainder by an intermediate or long-acting insulin.

Insulin dosage should be individualized to achieve/maintain a target blood glucose level and is determined by various factors including body weight, body fat, physical activity, insulin sensitivity, blood glucose levels, and target blood glucose.

Conventional regimen: The total daily insulin dose is administered as a mixture of rapid/short-acting and intermediate-acting insulins in 1 to 2 injections. Twice daily injections are preferred for better glycemic control. With the 2-injection regimen, generally two-thirds of the daily dose is given before breakfast and one-third is given before the evening meal.

Intensive regimen: The total daily dose is administered as 3 or more injections or by continuous subcutaneous infusion to cover basal and pre-meal bolus insulin requirements. The basal requirement is approximately 30 to 50% of the total dose, given as intermediate or long-acting insulin (NPH, zinc, extended zinc, lispro-protamine, glargine), 1 to 2 times daily. Meal boluses are approximately 50 to 70% of the total dose, given as rapid/short-acting insulin (regular, aspart, lispro) 2-5 times daily before meals. Common regimens include injections of rapid/short acting insulin before each meal along with injections of intermediate or long-acting insulin in the morning and/or evening. Dosage adjustments are made to achieve target blood glucose levels and are based on frequent blood glucose measurements, diet and exercise levels.

Total daily insulin requirements:
Initial dose: 0.5 to 0.8 unit/kg/day subcutaneously
Honeymoon phase: 0.2 to 0.5 unit/kg/day subcutaneously
Split dose therapy: 0.5 to 1.2 unit/kg/day subcutaneously
Insulin resistance: 0.7 to 2.5 units/kg/day subcutaneously

Usual Adult Dose for Diabetes Mellitus Type II:

Insulin aspart is a short acting insulin with a rapid onset and should be given immediately before meals. 50 to 70% of the daily insulin requirement may be provided by aspart and the remainder by an intermediate or long-acting insulin.

Diet and lifestyle modifications are recommended as initial treatment for type II diabetes, followed by oral agents. Insulin may be considered if patients are very hyperglycemic or symptomatic and/or not controlled with oral agents. Insulin may exacerbate obesity, further increase insulin resistance, and increase the frequency of hypoglycemia.

Insulin dosage should be individualized to achieve/maintain a target blood glucose level and is determined by various factors including body weight, body fat, physical activity, insulin sensitivity, blood glucose levels, and target blood glucose.

Conventional regimen:
Initial dose, monotherapy: Total insulin requirement: 0.1 unit/kg/day. When insulin is used alone, twice daily injections are recommended for better glycemic control. The total daily insulin dose is administered as a mixture of rapid/short-acting and intermediate-acting insulins in 1 to 2 injections. With the 2-injection regimen, generally two-thirds of the daily dose is given before breakfast and one-third is given before the evening meal. Once daily injections are sometimes used in children with suboptimal compliance; however, this may lead to more nocturia, fasting hyperglycemia, morning glucosuria, and a risk of ketoacidosis if the doses are missed.
Maintenance dose, monotherapy: Total daily insulin requirements may progress to 1.5 to 2.5 units/kg or higher in patients with obesity and insulin resistance.

Intensive regimen:
The necessity for and efficacy of intensive insulin therapy in type II diabetes has been controversial. The total daily dose is administered as 3 or more injections or by continuous subcutaneous infusion to cover basal and pre-meal bolus insulin requirements. This method may be appropriate for closely supervised and highly motivated older children or adolescents who are able to inject their insulin, monitor their blood glucose, and recognize hypoglycemia. The basal requirement is approximately 30 to 50% of the total dose, given as intermediate or long-acting insulin (NPH,zinc, extended zinc, lispro-protamine, glargine), 1 to 2 times daily. Meal boluses are approximately 50 to 70% of the total dose, given as rapid/short-acting insulin (regular, aspart, lispro) 2 to 5 times daily before meals. Common regimens include injections of rapid/short acting insulin before each meal along with injections of intermediate or long-acting insulin in the morning and/or evening. Dosage adjustments are made to achieve target blood glucose levels and are based on frequent blood glucose measurements, diet and exercise levels.
Initial dose, monotherapy: 0.5 to 1.5 unit/kg/day subcutaneously.
Maintenance dose, monotherapy: Total daily insulin requirements may progress to 2.5 units/kg or higher in patients with obesity and insulin resistance.

Usual Pediatric Dose for Diabetes Mellitus Type I:

>2 years:

Insulin aspart is a rapid-acting insulin and is given 2 to 5 times daily within 15 minutes before meals or as a continuous subcutaneous infusion via external insulin pump.

Insulin dosage should be individualized to achieve/maintain a target blood glucose level and is determined by various factors including body weight, body fat, physical activity, insulin sensitivity, blood glucose levels, and target blood glucose.

Conventional regimen: The total daily insulin dose is administered as a mixture of rapid/short-acting and intermediate-acting insulins in 1 to 2 injections. Twice daily injections are recommended for better glycemic control. With the 2-injection regimen, generally two-thirds of the daily dose is given before breakfast and one-third is given before the evening meal. Once daily injections are sometimes used in children with suboptimal compliance; however, this may lead to more nocturia, fasting hyperglycemia, morning glucosuria, and a risk of ketoacidosis if the doses are missed.

Intensive regimen: The total daily dose is administered as 3 or more injections or by continuous subcutaneous infusion to cover basal and pre-meal bolus insulin requirements. This method may be appropriate for closely supervised and highly motivated older children or adolescents who are able to inject their insulin, monitor their blood glucose, and recognize hypoglycemia. The basal requirement is approximately 30 to 50% of the total dose, given as intermediate or long-acting insulin (NPH, zinc, extended zinc, glargine), 1 to 2 times daily. Meal boluses are approximately 50 to 70% of the total dose, given as rapid/short-acting insulin (regular, lispro) 2 to 5 times daily before meals. Common regimens include injections of rapid/short acting insulin before each meal along with injections of intermediate or long-acting insulin in the morning and/or evening. Dosage adjustments are made to achieve target blood glucose levels and are based on frequent blood glucose measurements, diet and exercise levels.

Total daily insulin requirements:
Initial dose: 0.5 to 0.8 unit/kg/day subcutaneously
Honeymoon phase: 0.2 to 0.5 unit/kg/day subcutaneously
Split dose therapy: 0.5 to 1.2 unit/kg/day subcutaneously
Adolescents during growth spurts. 0.8 to 1.5 units/kg/day subcutaneously

Usual Pediatric Dose for Diabetes Mellitus Type II:

>2 years:

Insulin aspart is a rapid-acting insulin and should be given within 15 minutes before meals or as a continuous subcutaneous infusion via external insulin pump.

Diet and lifestyle modifications are recommended as initial treatment for type II diabetes, followed by oral agents (metformin). Insulin may be considered if children are very hyperglycemic or symptomatic and/or not controlled with oral agents. Insulin may exacerbate obesity, further increase insulin resistance, and increase the frequency of hypoglycemia.

Insulin dosage should be individualized to achieve/maintain a target blood glucose level and is determined by various factors including body weight, body fat, physical activity, insulin sensitivity, blood glucose levels, and target blood glucose.

Conventional regimen:
Initial dose, monotherapy: Total insulin requirement: 0.1 unit/kg/day. When insulin is used alone, twice daily injections are recommended for better glycemic control. The total daily insulin dose is administered as a mixture of rapid/short-acting and intermediate-acting insulins in 1 to 2 injections. With the 2-injection regimen, generally two-thirds of the daily dose is given before breakfast and one-third is given before the evening meal. Once daily injections are sometimes used in children with suboptimal compliance; however, this may lead to more nocturia, fasting hyperglycemia, morning glucosuria, and a risk of ketoacidosis if the doses are missed.
Maintenance dose, monotherapy: Total daily insulin requirements may progress to 1.5 to 2.5 units/kg or higher in patients with obesity and insulin resistance.

Intensive regimen:
The necessity for and efficacy of intensive insulin therapy in type II diabetes has been controversial. The total daily dose is administered as 3 or more injections or by continuous subcutaneous infusion to cover basal and pre-meal bolus insulin requirements. This method may be appropriate for closely supervised and highly motivated older children or adolescents who are able to inject their insulin, monitor their blood glucose, and recognize hypoglycemia. The basal requirement is approximately 30 to 50% of the total dose, given as intermediate or long-acting insulin (NPH, zinc, extended zinc, glargine), 1 to 2 times daily. Meal boluses are approximately 50 to 70% of the total dose, given as rapid/short-acting insulin (regular, lispro) 2 to 5 times daily before meals. Common regimens include injections of rapid/short acting insulin before each meal along with injections of intermediate or long-acting insulin in the morning and/or evening. Dosage adjustments are made to achieve target blood glucose levels and are based on frequent blood glucose measurements, diet and exercise levels.
Initial dose, monotherapy: 0.5 to 1.5 unit/kg/day subcutaneously.
Maintenance dose, monotherapy: Total daily insulin requirements may progress to 2.5 units/kg or higher in patients with obesity and insulin resistance.

What other drugs will affect insulin aspart?

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

• 
  

  albuterol (Proventil, Ventolin);

  
  


• 
  

  clonidine (Catapres);

  
  


• 
  

  reserpine;

  
  


• 
  

  guanethidine (Ismelin); or

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), timolol (Blocadren), and others.

  
  

There are many other medicines that can increase or decrease the effects of insulin aspart on lowering your blood sugar. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

More insulin aspart resources

• Insulin aspart Use in Pregnancy & Breastfeeding
• Insulin aspart Drug Interactions
• Insulin aspart Support Group
• 4 Reviews for Insulin aspart - Add your own review/rating

• Insulin Aspart Monograph (AHFS DI)


• Insulin Aspart Cartridges MedFacts Consumer Leaflet (Wolters Kluwer)


• NovoLog Consumer Overview


• Novolog Cartridges MedFacts Consumer Leaflet (Wolters Kluwer)


• Novolog Advanced Consumer (Micromedex) - Includes Dosage Information

Compare insulin aspart with other medications

• Diabetes, Type 1
• Diabetes, Type 2

Where can I get more information?

• Your pharmacist can provide more information about insulin aspart.