Pentacel

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

Included as part of the PRECAUTIONS section.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Pentacel, there are no specific foods that you must exclude from your diet when receiving this medication. 

Pentacel is given by a healthcare provider as a single 0.5-mL dose injected into the upper arm. 

Pentacel vaccine is to be administered as a 4 dose series at 2, 4, 6 and 15-18 months of age. The first dose may be given as early as 6 weeks of age.

Mixed vaccinations:

• Pentacel vaccine may be used to complete the first 4 doses of the 5-dose DTaP series in infants and children who have received 1 or more doses of Daptacel vaccine and are also scheduled to receive the other antigens of Pentacel vaccine. However, data are not available on the safety and effectiveness of such mixed sequences of Pentacel vaccine and Daptacel vaccine for successive doses of the primary DTaP series. Children who have completed a 4-dose series with Pentacel vaccine should receive a fifth dose of DTaP vaccine using Daptacel at 4-6 years of age.
• Pentacel vaccine may be used in infants and children who have received 1 or more doses of another licensed IPV vaccine and are scheduled to receive the antigens of Pentacel vaccine. However, data are not available on the safety and effectiveness of Pentacel vaccine in such infants and children.
• Pentacel vaccine may be used to complete the vaccination series in infants and children previously vaccinated with one or more doses of Haemophilus b Conjugate Vaccine (either separately administered or as part of another combination vaccine), who are also scheduled to receive the other antigens of Pentacel vaccine. However, data are not available on the safety and effectiveness of Pentacel vaccine in such infants and children. 

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Your child should not receive a booster vaccine if he or she had a life-threatening allergic reaction after the first shot. Keep track of any and all side effects your child has after receiving this vaccine. When the child receives a booster dose, you will need to tell the doctor if the previous shot caused any side effects.

Becoming infected with diphtheria, haemophilus B, pertussis, polio, or tetanus is much more dangerous to your child's health than receiving this vaccine. However, like any medicine, this vaccine can cause side effects but the risk of serious side effects is extremely low.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if the child has any of these side effects:

• irritability, crying for an hour or longer;

• very high fever; or

• extreme drowsiness, fainting.

Common side effects may include:

• low fever, mild fussiness; or

• redness, pain, tenderness, or swelling where the shot was given.

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 vaccine side effects to the US Department of Health and Human Services at 1-800-822-7967.

. Immunization Series

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

Mixed Sequences of Pentacel Vaccine and DTaP Vaccine

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

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

Mixed Sequences of Pentacel Vaccine and IPV Vaccine

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

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

Mixed Sequences of Pentacel Vaccine and Haemophilus b Conjugate Vaccine

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

. Administration

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

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

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

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

Do not administer this product intravenously or subcutaneously.

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

. Hypersensitivity

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

. Encephalopathy

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

. Progressive Neurologic Disorder

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

. Data from Clinical Studies

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

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

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

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

Solicited Adverse Reactions

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

Hypotonic Hyporesponsive Episodes

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

Seizures

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

Serious Adverse Events

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

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

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

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

. Data from Post-Marketing Experience

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

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

• Cardiac disorders
  Cyanosis
• Gastrointestinal disorders
  Vomiting, diarrhea
• General disorders and administration site conditions
  Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H influenzae type b disease)
• Immune system disorders
  Hypersensitivity (such as rash and urticaria)
• Infections and infestations
  Meningitis, rhinitis, viral infection
• Metabolism and nutrition disorders
  Decreased appetite
• Nervous system disorders
  Somnolence, HHE, depressed level of consciousness
• Psychiatric disorders
  Screaming
• Respiratory, thoracic and mediastinal disorders
  Apnea, cough
• Skin and subcutaneous tissue disorders
  Erythema, skin discoloration
• Vascular disorders
  Pallor

. Concomitant Administration with Other Vaccines

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

. Immunosuppressive Treatments

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

. Drug/Laboratory Test Interactions

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

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

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

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

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

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

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

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

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

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

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

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

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure your child receives all recommended doses of Pentacel. Your child may not be fully protected if he or she does not receive the full series.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Applies to diphtheria toxoid / haemophilus b conjugate (prp-t) vaccine / pertussis, acellular / poliovirus vaccine, inactivated / tetanus toxoid: intramuscular powder for suspension, intramuscular suspension

Along with its needed effects, diphtheria toxoid / haemophilus b conjugate (prp-t) vaccine / pertussis, acellular / poliovirus vaccine, inactivated / tetanus toxoid may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking diphtheria toxoid / haemophilus b conjugate (prp-t) vaccine / pertussis, acellular / poliovirus vaccine, inactivated / tetanus toxoid:

• Abdominal or stomach pain
• chest pain
• confusion
• coughing or shortness of breath
• crying, persistent and inconsolable, occurring within 48 hours and lasting 3 or more hours
• decreased urination
• diarrhea
• dizziness
• dry mouth
• fainting
• fever
• increase in heart rate
• lightheadedness
• loss of appetite
• nausea
• noisy breathing
• rapid breathing
• shortness of breath
• sneezing
• sore throat
• sunken eyes
• thirst
• tightness in the chest
• unusual tiredness or weakness
• wrinkled skin

• Bluish color of the fingernails, lips, skin, palms, or nail beds
• chills
• cold or flu-like symptoms
• drowsiness
• fast heartbeat
• general feeling of illness
• hives
• hoarseness
• irritation
• itching
• joint pain, stiffness, or swelling
• rash
• redness of the skin
• runny nose
• severe headache
• slow breathing
• sneezing
• stiff neck or back
• stuffy nose
• swelling of the eyelids, face, lips, hands, or feet

Some side effects of diphtheria toxoid / haemophilus b conjugate (prp-t) vaccine / pertussis, acellular / poliovirus vaccine, inactivated / tetanus toxoid may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Irritability
• tenderness at the injection site
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• change in skin color at the injection site
• paleness of the skin
• sleepiness or unusual drowsiness
• vomiting