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Tell your doctor about all prescription, nonprescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially those listed in the Actemra Warnings section above, and any of the following:
- Blood thinners, such as Coumadin, Jantoven (warfarin)
- Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as Advil or Motrin (ibuprofen) and Aleve or Naprosyn (naproxen)
- Medications that contain statins (cholesterol-lowering medication), such as Lipitor or Caduet (atorvastatin), Altoprev, Mevacor, or Advicor (lovastatin), and Zocor or Vytorin (simvastatin)
- Oral contraceptives (birth control pills)
- Elixophyllin, Theo-24, Theo-Dur or Uniphyl (theophylline)
What other information should I know?
Ask your pharmacist any questions you have about tocilizumab injection.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Is tocilizumab safe to take if I'm pregnant or breastfeeding?
There are no adequate studies of tocilizumab in pregnant women.
It is not known whether tocilizumab is excreted in breast milk.
What should I discuss with my healthcare provider before I receive tocilizumab?
You should not use tocilizumab if you are allergic to it.
Tell your doctor if you have ever had tuberculosis, if anyone in your household has tuberculosis, or if you have recently traveled to an area where certain infections are common (Ohio River Valley, Mississippi River Valley, and the Southwest).
Tell your doctor if you have any signs of infection such as fever, chills, cough, body aches, tiredness, open sores or skin wounds, diarrhea, stomach pain, weight loss, painful urination, or coughing up blood.
To make sure tocilizumab is safe for you, tell your doctor if you have ever had:
an infection such as herpes, pneumonia, or yeast infection;
diverticulitis, stomach ulcer, or stomach or intestinal bleeding;
HIV or AIDS;
a weak immune system;
hepatitis B (or if you are a carrier of the virus);
a nerve-muscle disease such as multiple sclerosis;
if you have received or are scheduled to receive any vaccines.
Treatment with tocilizumab may increase your risk of developing certain types of cancer. Talk to your doctor about your specific risk.
It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.
If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of tocilizumab on the baby.
It is not known whether tocilizumab passes into breast milk. You should not breast-feed while you are using tocilizumab.
Uses For Actemra
Tocilizumab injection is used alone or together with other medicines to reduce the signs and symptoms of moderate to severe active rheumatoid arthritis. This medicine helps keep joint damage from getting worse after other medicines (eg, adalimumab, etanercept, infliximab) have been used and did not work well. It is a monoclonal antibody.
Tocilizumab injection is also used alone or together with glucocorticoids (steroid medicine) to treat giant cell arteritis (inflammation of the arteries). It can be used alone after stopping treatment with glucocorticoids.
Tocilizumab injection is also used to treat polyarticular juvenile idiopathic arthritis (PJIA) and systemic juvenile idiopathic arthritis (SJIA) in children 2 years of age and older.
This medicine is available only with your doctor's prescription.
Proper Use of Actemra
A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins to treat rheumatoid arthritis, PJIA, or SJIA. It must be given slowly, so the needle will remain in place for at least 1 hour.
Tocilizumab injection may also be given as a shot under your skin to treat rheumatoid arthritis or giant cell arteritis. It may sometimes be given at home to patients who do not need to be in the hospital or clinic. If you are using this medicine at home, your doctor or nurse will teach you how to inject the medicine. Be sure that you understand exactly how to use this.
This medicine comes with a Medication Guide and patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.
This medicine is available in 2 forms. You may use a prefilled syringe or a vial (glass container).
If you use this medicine at home, you will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas. This will help prevent skin problems.
Allow the medicine to warm to room temperature for 30 minutes before using it.
If the medicine in the prefilled syringe has changed color, or if you see particles in it, do not use it. It should be clear and colorless or slightly yellow.
Throw away used syringes in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For injection dosage form (prefilled syringe):
- For giant cell arteritis:
- Adults—162 milligrams (mg) injected under the skin once a week or once every other week.
- Children—Use and dose must be determined by your doctor.
- For moderate to severe rheumatoid arthritis:
- Adults weighing 100 kilograms (kg) and above—162 milligrams (mg) injected under the skin once a week.
- Adults weighing less than 100 kg—At first, 162 mg injected under the skin once every other week. Your doctor may increase the dose to 162 mg once a week if needed.
- Children—Use and dose must be determined by your doctor.
- For giant cell arteritis:
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Store in the refrigerator. Do not freeze.
Protect the medicine from direct light. Keep your medicine in the original package until you are ready to use it.
Actemra Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur:More common
- Black, tarry stools
- bloody or cloudy urine
- blurred vision
- body aches or pain
- chest pain
- cough with or without mucus
- difficult, burning, or painful urination
- difficulty breathing
- difficulty swallowing
- ear congestion
- fast heartbeat
- feeling of warmth
- fever or chills
- frequent urge to urinate
- hives, itching, skin rash
- loss of appetite
- loss of consciousness
- loss of voice
- lower back or side pain
- nasal congestion
- pain or tenderness around the eyes and cheekbones
- painful blisters on the trunk of the body
- pale skin
- pounding in the ears
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- redness of the face, neck, arms, and occasionally, upper chest
- slow or fast heartbeat
- sore throat
- stomach pain
- stuffy or runny nose
- sudden sweating
- tightness of the chest
- ulcers, sores, or white spots in the mouth
- unusual bleeding or bruising
- unusual tiredness or weakness
- Bladder pain
- burning feeling in the chest or stomach
- dark urine
- decrease in height
- difficulty moving
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
- fast, irregular, pounding, or racing heartbeat or pulse
- feeling hot
- general feeling of discomfort or illness
- itching, pain, redness, swelling, tenderness, or warmth on the skin at the injection site
- joint pain
- light-colored stools
- muscle aches and pains
- muscle cramps or stiffness
- pain in the back, ribs, arms, legs, or groin or genitals
- pale skin
- severe stomach pain
- sharp back pain just below the ribs
- stomach upset
- swollen joints
- swollen, painful, or tender lymph glands in the face, neck, armpit, or groin
- tenderness in the stomach area
- trouble with sleeping
- troubled breathing with exertion
- unexplained runny nose or sneezing
- yellow eyes and skin
- changes in skin color
- coughing or spitting up blood
- gaseous stomach pain
- neck pain
- night sweats
- noisy breathing
- rapid, shallow breathing
- recurrent fever
- red, tender, or oozing skin at the wounded area
- sudden high fever or low-grade fever for months
- swelling of the foot or leg
- weight loss
- Dilated neck veins
- extreme fatigue
- severe stomach pain, cramping, or burning
- swelling of the face, fingers, feet, or lower legs
- vomiting of material that looks like coffee grounds, severe and continuing
- weight gain
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Burning, dry, or itching eyes
- discharge, excessive tearing
- redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
- skin rash, encrusted, scaly and oozing
- swelling or inflammation of the mouth
- warmth on the skin
- Abnormal or decreased touch sensation
- accumulation of pus
- bleeding or redness and swelling of the gums
- blemishes on the skin
- bloody eye
- chapped, red, or swollen lips
- feeling of constant movement of self or surroundings
- irritation in the mouth
- loose teeth
- persistent breath odor or bad taste in your mouth
- redness of the eye or skin
- redness or swelling in the ear
- scaling, redness, burning, pain, or other signs of inflammation on the lips
- sensation of spinning
- sore mouth or tongue
- swollen, red, or tender area of infection
- white patches in the mouth or on the tongue
- Bleeding after passing stool
- bloody nose
- burning, numbness, tingling, or painful sensations
- change in hearing
- continuing ringing or buzzing or other unexplained noise in the ears
- coughing or spitting up blood
- decreased vision or other changes in vision
- dry mouth
- ear drainage
- flushed, dry skin
- fruit-like breath odor
- hearing loss
- increased hunger, thirst, urination
- itching ears
- loss of consciousness
- uncomfortable swelling around the anus
- unexplained weight loss
- unsteadiness or awkwardness
- weakness in the arms, hands, legs, or feet
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Concomitant Drugs for Treatment of Adult Indications
In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg Actemra with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Actemra has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.1)].
In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.
Interactions with CYP450 Substrates
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of Actemra, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Actemra, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Actemra with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)].
Avoid use of live vaccines concurrently with Actemra [see Warnings and Precautions (5.8)].
Use in specific populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Actemra during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
The limited available data with Actemra in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Fetal/Neonatal adverse reactions
Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Actemra in utero [see Warnings and Precautions (5.8 )]
An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.
No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of Actemra to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Actemra and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.
Actemra by intravenous use is indicated for the treatment of pediatric patients with:
- Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
- Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
- Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older.
Safety and effectiveness of Actemra in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
In the retrospective analysis of pooled outcome data for patients treated with Actemra for CAR T cell-induced CRS, 25 patients were children (2 years up to 12 years of age), and 17 patients were adolescents (12 years up to 18 years of age). There were no differences between the pediatric patients and the adults for safety or efficacy.
Of the 2644 patients who received Actemra in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received Actemra-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among Actemra treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Clinical studies that included Actemra for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
The safety and efficacy of Actemra have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.7)].
No dose adjustment is required in patients with mild or moderate renal impairment. Actemra has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
PRINCIPAL DISPLAY PANEL - 4 mL Vial Box
80 mg/4 mL
For Intravenous Infusion only after
Single-Use Vial; Discard unused portion
ATTENTION PROVIDER: Each patient is
required to receive the enclosed
Actemra Food Interactions
Medicines 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 Actemra, there are no specific foods that you must exclude from your diet when receiving Actemra.
Mechanism of Action
Interleukin-6 receptor antagonist; changes in clinical trials observed include decreased C-reactive protein level to within normal range, decreased values in other pharmacodynamic parameters (eg, rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and increased hemoglobin value
Peak plasma time: 1 hr
Half-life: up to 11 days (4 mg/kg); up to 13 days (8 mg/kg)
Cmax: 88.3 mcg/mL (4 mg/kg); 183 mcg/mL (8 mg/kg)
Clearance: 0.0125 L/hr
The following serious adverse reactions are described elsewhere in labeling:
- Serious Infections [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Perforations [see WARNINGS AND PRECAUTIONS]
- Laboratory Parameters [see WARNINGS AND PRECAUTIONS]
- Immunosuppression [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions, Including Anaphylaxis [see WARNINGS AND PRECAUTIONS]
- Demyelinating Disorders [see WARNINGS AND PRECAUTIONS]
- Active Hepatic Disease and Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV)
The ACTEMRA-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of ACTEMRA-IV 8 mg per kg monotherapy (288 patients), ACTEMRA-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or ACTEMRA-IV 4 mg per kg in combination with methotrexate (774 patients).
The all exposure population includes all patients in registration studies who received at least one dose of ACTEMRA-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.
All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.
The most common serious adverse reactions were serious infections [see WARNINGS AND PRECAUTIONS]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with ACTEMRA-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking ACTEMRA-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of ACTEMRA-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.Overall Infections
In the 24 week, controlled clinical studies, the rate of infections in the ACTEMRA-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.
The overall rate of infections with ACTEMRA-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.Serious Infections
In the 24 week, controlled clinical studies, the rate of serious infections in the ACTEMRA-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.
In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see WARNINGS AND PRECAUTIONS].Gastrointestinal Perforations
During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with ACTEMRA-IV therapy.
In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see WARNINGS AND PRECAUTIONS]. The relative contribution of these concomitant medications versus ACTEMRA-IV to the development of GI perforations is not known.Infusion Reactions
In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.Anaphylaxis
Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with ACTEMRA-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of ACTEMRA-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see WARNINGS AND PRECAUTIONS].Laboratory Abnormalities
In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm³ occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm³ occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm³ occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm³ and the occurrence of serious infections.
In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see WARNINGS AND PRECAUTIONS].
In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm³ occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.
In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see WARNINGS AND PRECAUTIONS].
Elevated Liver Enzymes
Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of ACTEMRA-IV, or reduction in ACTEMRA-IV dose, resulted in decrease or normalization of liver enzymes [see DOSAGE AND ADMINISTRATION]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see WARNINGS AND PRECAUTIONS].
Table 1 : Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V*
|ACTEMRA 8 mg per kg MONOTHERAPY |
N = 288 (%)
N = 284 (%)
|ACTEMRA 4 mg per kg + DMARDs |
N = 774 (%)
|ACTEMRA 8 mg per kg + DMARDs |
N = 1582 (%)
|Placebo + DMARDs |
N = 1170 (%)
|> ULN to 3x ULN||22||26||34||41||17|
|> 3x ULN to 5x ULN||0.3||2||1||2||0.3|
|> 5x ULN||0.7||0.4||0.1||0.2||< 0.1|
|> ULN to 3x ULN||36||33||45||48||23|
|> 3x ULN to 5x ULN||1||4||5||5||1|
|> 5x ULN||0.7||1||1.3||1.5||0.3|
|ULN = Upper Limit of Normal |
*For a description of these studies, see Section 14, Clinical Studies.
In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials
Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:
- Mean LDL increased by 13 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 20 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 25 mg per dL in ACTEMRA 8 mg per kg monotherapy.
- Mean HDL increased by 3 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 5 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 4 mg per dL in ACTEMRA 8 mg per kg monotherapy.
- Mean LDL/HDL ratio increased by an average of 0.14 in the ACTEMRA 4 mg per kg+DMARD arm, 0.15 in the ACTEMRA 8 mg per kg+DMARD, and 0.26 in ACTEMRA 8 mg per kg monotherapy.
- ApoB/ApoA1 ratios were essentially unchanged in ACTEMRA-treated patients.
Elevated lipids responded to lipid lowering agents.
In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.
During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRA-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the ACTEMRA-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see WARNINGS AND PRECAUTIONS].Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg ACTEMRA-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.
Table 2 : Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD
|24 Week Phase 3 Controlled Study Population|
|Preferred Term||ACTEMRA 8 mg per kg MONOTHERAPY |
N = 288 (%)
N = 284 (%)
|ACTEMRA 4 mg per kg + DMARDs |
N = 774 (%)
|ACTEMRA 8 mg per kg + DMARDs |
N = 1582 (%)
|Placebo + DMARDs |
N = 1170 (%)
|Upper Respiratory Tract Infection||7||5||6||8||6|
|Abdominal Pain Upper||2||2||3||3||2|
Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with ACTEMRA-IV in controlled trials were:
Infections and Infestations: oral herpes simplex
Gastrointestinal disorders: stomatitis, gastric ulcer
Investigations: weight increased, total bilirubin increased
Blood and lymphatic system disorders: leukopenia
General disorders and administration site conditions: edema peripheral
Respiratory, thoracic, and mediastinal disorders: dyspnea, cough
Eye disorders: conjunctivitis
Renal disorders: nephrolithiasis
Endocrine disorders: hypothyroidism
Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Subcutaneous ACTEMRA (ACTEMRA-SC)
The ACTEMRA-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.
The safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions, which were more common with ACTEMRA-SC compared with placebo SC injections (IV arm).Injection Site Reactions
In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC ACTEMRA and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.Immunogenicity
In the 6-month control period in SC-I, 0.8% (5/625) in the ACTEMRA-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the ACTEMRA-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the ACTEMRA-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.
A total of 1454 (>99%) patients who received ACTEMRA-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.
The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.Laboratory Abnormalities
During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 ï¿½ 109/L occurred in 2.9% and 3.7% of patients receiving ACTEMRA-SC weekly and every other week, respectively.
There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.
During routine laboratory monitoring in the ACTEMRA-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm³.
Elevated Liver Enzymes
During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving ACTEMRA-SC weekly and 3.4% and 0.7% receiving ACTEMRA SC every other week.
Lipid Parameters Elevations
During routine laboratory monitoring in the ACTEMRA-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving ACTEMRA-SC weekly, every other week and placebo, respectively.
Clinical Trials Experience In Giant Cell Arteritis Patients Treated With Subcutaneous ACTEMRA (ACTEMRA-SC)
The safety of subcutaneous ACTEMRA (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the ACTEMRA GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the ACTEMRA treatment groups was generally consistent with the known safety profile of ACTEMRA. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the ACTEMRA weekly group and 160.2/4.4 events per 100 patient years in the ACTEMRA every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups.
Clinical Trials Experience In Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV)
The safety of ACTEMRA-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the ACTEMRA-IV all exposure population (defined as patients who received at least one dose of ACTEMRA-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see ADVERSE REACTIONS].Infections
The rate of infections in the ACTEMRA-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).Infusion Reactions
In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the ACTEMRA-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see ADVERSE REACTIONS].
No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.Immunogenicity
One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.Laboratory Abnormalities
During routine laboratory monitoring in the ACTEMRA-IV all exposure population, a decrease in neutrophil counts below 1 ï¿½ 109 per L occurred in 3.7% of patients.
There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections.
During routine laboratory monitoring in the ACTEMRA-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm³ without associated bleeding events.
Elevated Liver Enzymes
During routine laboratory monitoring in the ACTEMRA-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively.
During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%).
Clinical Trials Experience In Systemic Juvenile Idiopathic Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV)
The data described below reflect exposure to ACTEMRA-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with ACTEMRA-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with ACTEMRA-IV in the open-label extension phase.
The most common adverse events (at least 5%) seen in ACTEMRA-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.Infections
In the 12 week controlled phase, the rate of all infections in the ACTEMRA-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.
In the 12 week controlled phase, the rate of serious infections in the ACTEMRA-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.Macrophage Activation Syndrome
In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with ACTEMRA-IV. One patient in the placebo group escaped to ACTEMRA-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had ACTEMRA-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the ACTEMRA-IV SJIA clinical development experience; however no definitive conclusions can be made.Infusion Reactions
Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of ACTEMRA-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
Within 24 hours after infusion, 16% of patients in the ACTEMRA-IV treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.Anaphylaxis
Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with ACTEMRA-IV during the controlled and open label extension study [see WARNINGS AND PRECAUTIONS].Immunogenicity
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.Laboratory Abnormalities
During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 ï¿½ 109 per L occurred in 7% of patients in the ACTEMRA-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the ACTEMRA-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections.
During routine monitoring in the 12 week controlled phase, 1% of patients in the ACTEMRA-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm³.
In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the ACTEMRA-IV group, with no associated bleeding.
Elevated Liver Enzymes
During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the ACTEMRA-IV group and in 0% of placebo patients.
In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of ACTEMRA-IV treated patients, respectively.
During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN - 2x ULN occurred in 1.5% of the ACTEMRA-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN - 2x ULN occurred in 1.9% of patients in the ACTEMRA-IV group and 0% of the placebo group.
In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.
Clinical Trials Experience In Patients With Cytokine Release Syndrome Treated With Intravenous ACTEMRA (ACTEMRA-IV)
In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered. No adverse reactions related to tocilizumab were reported [see Clinical Studies].
The following adverse reactions have been identified during post-approval use of intravenous ACTEMRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Fatal anaphylaxis [see WARNINGS AND PRECAUTIONS]
- Stevens-Johnson Syndrome
Read the entire FDA prescribing information for Actemra (Tocilizumab Injection)Read More »
How is Actemra given?
Before you start treatment with Actemra, your doctor may perform tests to make sure you do not have tuberculosis or other infections.
Actemra is injected into a vein through an IV. A healthcare provider will give you this type of injection.
Actemra is sometimes injected under the skin. You may be shown how to use this type of injection at home using a prefilled syringe. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles and syringes.
Actemra is usually given every 1 to 4 weeks. Follow your doctor's instructions.
Use a disposable needle only once, then throw away 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.
Do not use Actemra if it has changed colors or has particles in it. Call your pharmacist for new medication.
Each Actemra prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.
Store the prefilled syringes in their original container in a refrigerator. Protect from moisture and light. Do not freeze. Throw away any prefilled syringes not used before the expiration date on the medicine label.
Actemra can lower blood cells that help your body fight infections and help your blood to clot. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Your injections may be delayed based on the results of these tests.
Some infections are more likely to occur in certain areas of the world. Tell your doctor where you live and where you have recently traveled or plan to travel to during treatment.
If you have ever had hepatitis B, Actemra can cause this condition to come back or get worse. You will need frequent blood tests to check your liver function during treatment and for several months after you stop using this medicine.
If you need surgery, tell the surgeon ahead of time that you are using Actemra. You may need to stop using the medicine for a short time.
Actemra can have long-lasting effects on your body. You may need certain medical tests every 6 months after you stop using this medication.
You may be treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.
Tocilizumab Pregnancy Warnings
This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: C US FDA pregnancy category: Not assigned. Risk Summary: The limited data with this drug in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies are actively transported across the placenta during the third trimester and may affect immune response in the in utero exposed infant. Animal studies showed that during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus. Comments: -Women of childbearing potential should use effective contraception during and up to 3 months after treatment with this drug.
Animal studies have shown no evidence for a teratogenic/dysmorphogenic effect at any dose, but there is an increased risk of spontaneous abortion/embryofetal death at high dose. There are no controlled data in human pregnancy. It is not known whether this drug can cause fetal harm or adversely affect reproductive capacity in humans. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to this drug during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972 or going to http://www.pregnancystudies.org/ongoing-pregnancy-studies/autoimmune-studies/. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.