Hyrimoz Drug Information

Recommended Tuberculosis Evaluation Prior to initiating HYRIMOZ and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection.

Recommended Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of HYRIMOZ for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with HYRIMOZ. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of HYRIMOZ to 40 mg every week or 80 mg every other week.

Recommended Dosage in Juvenile Idiopathic Arthritis or Pediatric Patients with Uveitis The recommended subcutaneous dosage of HYRIMOZ for pediatric patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) or pediatric uveitis, based on weight, is shown below. Adalimumab products have not been studied in patients with polyarticular JIA or pediatric uveitis less than 2 years of age or in patients with a weight below 10 kg.

Recommended Dosage in Crohn’s Disease Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of HYRIMOZ for adult patients with moderately to severely active Crohn’s disease (CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a dosage of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with HYRIMOZ.

Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with HYRIMOZ if necessary. Discontinue HYRIMOZ in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy.

Recommended Dosage in Plaque Psoriasis or Adults with Uveitis The recommended subcutaneous dosage of HYRIMOZ for adult patients with plaque psoriasis (Ps) or uveitis (UV) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

Recommended Dosage in Hidradenitis Suppurativa Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of HYRIMOZ for adult patients with moderate to severe hidradenitis suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly or 80 mg every other week dosing two weeks later (Day 29). Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of HYRIMOZ for pediatric patients 12 years of age and older weighing at least 30 kg with moderate to severe hidradenitis suppurativa (HS), based on body weight, is shown below:

General Considerations for Administration HYRIMOZ is intended for use under the guidance and supervision of a physician. A patient may self-inject HYRIMOZ or a caregiver may inject HYRIMOZ using either the HYRIMOZ single-dose prefilled Sensoready Pen or the HYRIMOZ single-dose prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. HYRIMOZ can be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature.

Do not remove the cap while allowing it to reach room temperature. Carefully inspect the solution in the HYRIMOZ single-dose prefilled Sensoready Pen or HYRIMOZ single-dose prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. The solution should be clear, colorless or slightly yellowish.

Do not use a prefilled syringe or prefilled Sensoready Pen if the solution is cloudy, discolored, or has flakes or particles in it. HYRIMOZ does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. Instruct patients using the HYRIMOZ single-dose prefilled Sensoready Pen and the HYRIMOZ single-dose prefilled syringe to inject the full amount according to the directions provided in the Instructions for Use.

Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard. If a dose is missed, administer the dose as soon as possible.

Thereafter, resume dosing at the regular scheduled time.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of subjects treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of subjects receiving placebo.

Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of subjects who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in subjects with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for subjects taking adalimumab and 4% for placebo-treated subjects. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis. Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 adalimumab treated subjects, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB.

Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal.

Autoantibodies In the rheumatoid arthritis controlled trials, 12% of subjects treated with adalimumab and 7% of placebo-treated subjects that had negative baseline ANA titers developed positive titers at Week 24. Two subjects out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like syndrome. The subjects improved following discontinuation of therapy.

No subjects developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab products on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in subjects receiving TNF-blockers.

Since many of these subjects in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in subjects with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of adalimumab-treated subjects and 1.5% of control-treated subjects (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment.

No ALT elevations ≥ 3 x ULN occurred in the open-label study of adalimumab in subjects with polyarticular JIA who were 2 to <4 years. In the Phase 3 trial of adalimumab in pediatric subjects with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of subjects, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these subjects discontinued due to abnormalities in ALT tests. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to adalimumab in 2468 subjects, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV).

Adalimumab was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most subjects received 40 mg adalimumab every other week.

Table 1 summarizes reactions reported at a rate of at least 5% in subjects treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1.

Adverse Reactions Reported by ≥5% of Subjects Treated with Adalimumab During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Table 1. Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, adalimumab was studied in 171 subjects who were 4 to 17 years of age, with polyarticular JIA.

Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. Serious infections were observed in 4% of subjects within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. In Study JIA-I, 45% of subjects experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment.

The types of infections reported in adalimumab-treated subjects were generally similar to those commonly seen in polyarticular JIA subjects who are not treated with TNF blockers. A less commonly reported adverse event in subjects receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment. In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of subjects and included primarily localized allergic hypersensitivity reactions and allergic rash.

In Study JIA-I, 10% of subjects treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No subject developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of subjects treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I.

Elevations exceeding 5 times the upper limit of normal were observed in several subjects. CPK concentrations decreased or returned to normal in all subjects. Most subjects were able to continue adalimumab without interruption.

The safety profile for this population was similar to the safety profile seen in subjects 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of subjects experienced an infection while receiving adalimumab. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity.

Serious infections were observed in 9% of subjects receiving adalimumab in the study and included dental caries, rotavirus gastroenteritis, and varicella. In Study JIA-II, non-serious allergic reactions were observed in 6% of subjects and included intermittent urticaria and rash, which were all mild in severity. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies Adalimumab has been studied in 395 subjects with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 subjects with ankylosing spondylitis (AS) in two placebo-controlled studies.

The safety profile for subjects with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in subjects with RA, adalimumab Studies RA-I through IV. Crohn’s Disease Clinical Studies Adults: The safety profile of adalimumab in 1478 adult subjects with Crohn’s disease from four placebo-controlled and two open-label extension studies was similar to the safety profile seen in subjects with RA. Pediatric Patients 6 Years to 17 Years: The safety profile of adalimumab in 192 pediatric subjects from one double-blind study (Study PCD-I) and one open-label extension study was similar to the safety profile seen in adult subjects with Crohn’s disease.

A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I. A total of 5% of children experienced a serious infection while receiving adalimumab in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis.

In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions. Ulcerative Colitis Clinical Studies Adults: The safety profile of adalimumab in 1010 adult subjects with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study was similar to the safety profile seen in subjects with RA. Plaque Psoriasis Clinical Studies Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies.

The safety profile for subjects with Ps treated with adalimumab was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, adalimumab-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Hidradenitis Suppurativa Clinical Studies Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study.

The safety profile for subjects with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab. Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies. Uveitis Clinical Studies Adalimumab has been studied in 464 adult subjects with uveitis (UV) in placebo-controlled and open-label extension studies and in 90 pediatric subjects with uveitis (Study PUV-I).

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products. There are two assays that have been used to measure anti-adalimumab antibodies.

With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2.

Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with adalimumab Rheumatoid Arthritis and Psoriatic Arthritis: Subjects in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6 to 12 month period. No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, subjects receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing.

In subjects receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive subjects than among antibody-negative subjects. The long-term immunogenicity of adalimumab products is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of adalimumab products. 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 adalimumab products exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis, autoimmune hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction Vascular disorders: Systemic vasculitis, deep vein thrombosis

Methotrexate Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent clearance of adalimumab, the data do not suggest the need for dose adjustment of either HYRIMOZ or MTX.

Biological Products

In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF-blockers with anakinra or abatacept, with no added benefit; therefore, use of HYRIMOZ with abatacept or anakinra is not recommended in patients with RA. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information regarding the concomitant use of HYRIMOZ and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV.

Concomitant administration of HYRIMOZ with other biologic DMARDs (e.g., anakinra and abatacept) or other TNF-blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

Live Vaccines Avoid the use of live vaccines with HYRIMOZ.

Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HYRIMOZ in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

Pregnancy Risk Summary Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab. Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of 7.5% for major birth defects in the disease-matched comparison cohort.

The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects ( see Data ). Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant ( see Clinical Considerations ). In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations 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 2-4% and 15-20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester ( see Data ).

Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design. In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth.

The last dose of adalimumab was given between 1 and 56 days prior to delivery. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. Animal Data In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week).

Adalimumab did not elicit harm to the fetuses or malformations.

• Pediatric Use The safety and effectiveness of HYRIMOZ have not been established in pediatric patients with psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis. The safety and effectiveness of HYRIMOZ have been established for:
• Reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older.
• The treatment of moderately to severely active Crohn’s disease in pediatric patients 6 years of age and older.
• The treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.
• The treatment of non-infectious intermediate, posterior, and panuveitis in pediatric patients 2 years of age and older. Due to their inhibition of TNFα, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta. The clinical significance of elevated adalimumab concentrations in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants. Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products. Juvenile Idiopathic Arthritis The safety and effectiveness of HYRIMOZ for the treatment of moderately to severely active polyarticular JIA have been established in pediatric patients 2 years of age and older. Use for this indication is supported by evidence from an adequate and well-controlled study (Study JIA) of adalimumab in patients 4 to 17 years of age and a safety study (Study JIA-II) of adalimumab in patients 2 to < 4 years of age where the safety profile was similar to patients 4 to 17 years of age. Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. The safety of adalimumab in pediatric patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions. The safety and effectiveness of HYRIMOZ have not been established in pediatric patients with JIA less than 2 years of age. Pediatric Crohn’s Disease The safety and effectiveness of HYRIMOZ for the treatment of moderately to severely active Crohn’s disease have been established in pediatric patients 6 years of age and older. Use of HYRIMOZ for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age). The adverse reaction profile in patients 6 years to 17 years of age was similar to adults. The safety and effectiveness of HYRIMOZ have not been established in pediatric patients with Crohn’s disease less than 6 years of age. Pediatric Uveitis The safety and effectiveness of HYRIMOZ for the treatment of non-infectious, intermediate, posterior, and panuveitis have been established in pediatric patients 2 years of age and older. Use of HYRIMOZ for this indication is supported by evidence from adequate and well-controlled studies of adalimumab in adults and a 2:1 randomized, controlled clinical study of adalimumab in 90 pediatric patients. The safety and effectiveness of HYRIMOZ have not been established in pediatric patients with uveitis less than 2 years of age. Hidradenitis Suppurativa Use of HYRIMOZ in pediatric patients 12 years of age and older for the treatment of moderate to severe HS is supported by evidence from adequate and well-controlled studies of adalimumab in adult HS patients. Additional population pharmacokinetic modeling and simulation predicted that weight-based dosing of adalimumab in pediatric patients 12 years of age and older can provide generally similar exposure to adult HS patients. The course of HS is sufficiently similar in adult and adolescent patients to allow extrapolation of data from adult to adolescent patients. The recommended dosage in pediatric patients 12 years of age or older is based on body weight. The safety and effectiveness of HYRIMOZ have not been established in patients less than 12 years of age with HS.

Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdose management recommendations.