Isentress

• Raltegravir (Isentress) is an antiretroviral medicine approved for the treatment of human immunodeficiency virus (HIV) infection. Raltegravir is an integrase inhibitor similar to elvitegravir (Vitekta) and dolutegravir (Tivicay). Raltegravir slows the spread of HIV infection by blocking the HIV integrase enzyme required for virus multiplication. To improve the chance of fighting HIV-1 infection, raltegravir must be taken with other HIV medicines. Although raltegravir does not cure HIV or AIDS, continuous HIV treatment with raltegravir can help patients control the infection and decrease their risk of acquiring HIV-related illnesses. Raltegravir helps to improve the immune system by increasing the number of white blood cells called CD4+ (T) cells, and consequently reduce the risk of death or getting opportunistic infections that can happen when the immune system is weak.
• Raltegravir was initially approved by the FDA in October 2007.

• Use of raltegravir in pregnant women has not been adequately evaluated. Due to the lack of conclusive safety data, raltegravir should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Raltegravir is classified as FDA pregnancy risk category C.
• Breastfeeding is not recommended while taking raltegravir. To avoid transmitting the HIV-1 virus to the nursing infant, it is not recommended that HIV-1-infected mothers breastfeed their infants. It is not known if raltegravir is excreted into human milk.

• Film coated oral tablets: 400 mg
• Chewable oral tablets: 25 mg and 100 mg
• Granules for oral suspension: single use packet of 100 mg

• Raltegravir should be stored at room temperature between 20 C to 25 C (68 F to 77 F).
• For best protection the chewable tablets and granules for oral suspension should be stored in the original container.

Isentress is an anti-HIV (antiretroviral) medicine used for the treatment of human immunodeficiency virus (HIV), the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Isentress is used along with other anti-HIV medicines. Isentress will NOT cure HIV infection, however.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).1 200

Administration

Oral Administration

Raltegravir (Isentress): Administer orally twice daily without regard to food.1 Use in conjunction with other antiretrovirals.1

Lamivudine/raltegravir (Dutrebis): Administer orally twice daily without regard to food.241 Use in conjunction with other antiretrovirals.241

Because antiretrovirals in lamivudine/raltegravir may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated when the fixed combination used in conjunction with other antiretrovirals.241 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Raltegravir (Isentress): May be chewed or swallowed whole.1 If needed, 100-mg chewable tablet can be divided into equal halves.1

Used in pediatric patients weighing ≥11 kg to <25 kg.1 Also may be used as alternative in pediatric patients weighing ≥25 kg who cannot swallow film-coated tablets.1

Raltegravir (Isentress): Must be swallowed whole.1 Used in adults, adolescents, and pediatric patients weighing ≥25 kg.1

Lamivudine/raltegravir (Dutrebis): Used in adults, adolescents, and pediatric patients ≥6 years of age weighing ≥30 kg.241

Raltegravir (Isentress): Immediately prior to use, contents of a single-use packet of powder for oral suspension must be mixed in 5 mL of water to provide a suspension containing 20 mg/mL.1 Appropriate dosage of the suspension is then administered orally using dosing syringe provided by the manufacturer.1

To prepare oral suspension, use dosing syringe provided by the manufacturer to measure and add 5 mL of water to the mixing cup provided by the manufacturer.1 Open a single-dose packet of powder for oral suspension and pour entire contents into the mixing cup, tightly close mixing cup, and gently swirl for 30–60 seconds.1 Suspension will appear cloudy.1

Draw recommended dosage of oral suspension into the dosing syringe and administer orally.1

Administer within 30 minutes of mixing; discard any remaining suspension.1 After each use, handwash dosing syringe and mixing cup with warm water and dish soap, rinse with water, and air dry.1

Used in pediatric patients ≥4 weeks of age weighing ≥3 kg to <20 kg.1

Dosage

Available as raltegravir potassium; dosage expressed in terms of raltegravir.1 241

Single-entity raltegravir (Isentress) chewable tablets and oral suspension are not bioequivalent to single-entity raltegravir film-coated tablets;1 do not substitute chewable tablets or oral suspension for the 400-mg film-coated tablet.1

Lamivudine/raltegravir (Dutrebis): A film-coated tablet containing lamivudine 150 mg and raltegravir 300 mg provides lamivudine and raltegravir exposures comparable to those attained when a 150-mg lamivudine tablet is administered concomitantly with a 400-mg raltegravir tablet.241

Bioavailability of raltegravir contained in lamivudine/raltegravir is higher than that of raltegravir contained in single-entity raltegravir;241 the 300-mg raltegravir dose in lamivudine/raltegravir provides raltegravir exposures comparable to those provided by a 400-mg dose of single-entity raltegravir.241

Pediatric Patients

Raltegravir (Isentress) in infants and children ≥4 weeks of age weighing ≥3 kg to <20 kg (oral suspension): Dosage based on weight (approximately 6 mg/kg twice daily; up to 100 mg twice daily).1 (See Table 1.)

Raltegravir in pediatric patients weighing ≥11 kg to <25 kg (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to 300 mg twice daily).1 (See Table 1.)

Raltegravir in children and adolescents weighing ≥25 kg (film-coated tablets): 400 mg twice daily (one 400-mg film-coated tablet twice daily).1

Raltegravir in children and adolescents weighing ≥25 kg (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to 300 mg twice daily).1 (See Table 2.) Used as alternative in those who cannot swallow film-coated tablets.1

Lamivudine/raltegravir (Dutrebis) in children ≥6 years of age weighing ≥30 kg (film-coated tablets): 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Lamivudine/raltegravir in adolescents ≥16 years of age (film-coated tablets): 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Adults

Raltegravir (Isentress) film-coated tablets: 400 mg twice daily (one 400-mg film-coated tablet twice daily).1

Lamivudine/raltegravir (Dutrebis) film-coated tablets: 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Raltegravir (Isentress): 400 mg twice daily.199 Used in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV [PEP] under Uses).199

Initiate PEP as soon as possible following exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Raltegravir 400 mg twice daily.198 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Nonoccupational Exposure to HIV [nPEP] under Uses).198

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.198

nPEP not recommended if exposed individual seeks care ≥72 hours after exposure.198

Prescribing Limits

Pediatric Patients

Raltegravir (Isentress) oral suspension: Maximum 100 mg twice daily.1

Raltegravir (Isentress) chewable tablets: Maximum 300 mg twice daily.1

Lamivudine/raltegravir (Dutrebis) film-coated tablets: Maximum 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Adults

Lamivudine/raltegravir (Dutrebis) film-coated tablets: Maximum 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Special Populations

Hepatic Impairment

Raltegravir (Isentress): Dosage adjustments not needed in patients with mild to moderate hepatic impairment;1 200 not studied in those with severe hepatic impairment.1

Lamivudine/raltegravir (Dutrebis): Dosage adjustments not needed in patients with mild to moderate hepatic impairment.241 Safety and efficacy not established in those with decompensated liver disease.241 (See Hepatic Impairment under Cautions.)

Renal Impairment

Raltegravir (Isentress): Dosage adjustments not needed in patients with renal impairment.1 200 Avoid administering raltegravir before dialysis session.1 (See Renal Impairment under Cautions.)

Lamivudine/raltegravir (Dutrebis): Do not use in patients with Clcr <50 mL/minute since reduction in lamivudine dosage needed in such patients.241 (See Renal Impairment under Cautions.)

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Raltegravir is metabolized by UGT1A1.1 Does not inhibit UGT1A1 or 2B7 in vitro.1

Not a substrate for CYP isoenzymes.1 Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce CYP1A2, 2B6, or 3A4.1

Does not inhibit P-glycoprotein-mediated transport.1

The following drug interactions are based on studies using raltegravir and a study using lamivudine/raltegravir.241 When lamivudine/raltegravir used, consider interactions associated with both drugs in the fixed combination.241

Drugs Affecting or Metabolized by UGT

Raltegravir and lamivudine/raltegravir: Potential pharmacokinetic interactions with drugs that are potent inducers of UGT1A1 (decreased plasma concentrations of raltegravir)1 241 or inhibitors of UGT1A1 (increased plasma concentrations of raltegravir).1 241

Raltegravir and lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs that are substrates for UGT1A1 or 2B7.1 241

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Raltegravir: Pharmacokinetic interactions unlikely with drugs that are substrates for CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.1

Lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs metabolized by CYP isoenzymes.241

Drugs Affected by P-glycoprotein Transport

Raltegravir: Pharmacokinetic interactions unlikely with drugs that are substrates for P-glycoprotein (P-gp).1

Lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs that are P-gp substrates.241

Specific Drugs

• Raltegravir is an HIV INSTI antiretroviral.1 200 Inhibits activity of HIV integrase, an enzyme that integrates HIV DNA into the host cell genome.4 1 Inhibition of integrase prevents propagation of viral infection.1 4

• Active against HIV type 1 (HIV-1);1 200 also has some in vitro activity against HIV type 2 (HIV-2).1 200

• HIV-1 resistant to raltegravir have been produced in vitro1 and have emerged during raltegravir therapy.1 17 18

• Cross-resistance between raltegravir and other INSTIs (e.g., dolutegravir, elvitegravir) reported.19 20 21 22 23 235 242

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In the U.S.

• Isentress
• Isentress HD

Available Dosage Forms:

• Powder for Suspension
• Tablet, Chewable
• Tablet

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Integrase Inhibitor

• Film-coated Tablets
  • 400 mg pink, oval-shaped, film-coated tablets with "227" on one side (Isentress).
  • 600 mg yellow, oval-shaped, film-coated tablets with Merck logo and "242" on one side and plain on the other side (Isentress HD).
• Chewable Tablets
  • 100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score.
  • 25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side.
• For Oral Suspension
  • 100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.

Description of Clinical Studies

The evidence of durable efficacy of Isentress 400 mg twice daily is based on the analyses of 240-week data from a randomized, double-blind, active-controlled trial, STARTMRK evaluating Isentress 400 mg twice daily in antiretroviral treatment-naïve HIV-1 infected adult subjects, the analysis of 48-week data from a randomized, double-blind, active-control trial, ONCEMRK evaluating Isentress HD 1200 mg (2 × 600 mg) once daily in treatment-naïve adult subjects, and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2, evaluating Isentress 400 mg twice daily in antiretroviral treatment-experienced HIV-1 infected adult subjects. See Table 16.

Treatment-Naïve Adult Subjects

STARTMRK (Isentress 400 mg twice daily)

STARTMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of Isentress 400 mg twice daily versus efavirenz 600 mg at bedtime both with emtricitabine (+) tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; or >50,000 copies/mL) and by hepatitis status. In STARTMRK, 563 subjects were randomized and received at least 1 dose of either raltegravir 400 mg twice daily or efavirenz 600 mg at bedtime, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 563 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 37 years (range 19-71), 19% female, 58% non-white, 6% had hepatitis B and/or C virus co-infection, 20% were CDC Class C (AIDS), 53% had HIV-1 RNA greater than 100,000 copies per mL, and 47% had CD4+ cell count less than 200 cells per mm3; the frequencies of these baseline characteristics were similar between treatment groups.

ONCEMRK (Isentress HD 1200 mg [2 × 600 mg] once daily)

ONCEMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of Isentress HD 1200 mg (2 × 600 mg) once daily versus Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-1-infected subjects with HIV-1 RNA ≥1000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and by hepatitis B and C infection status.

In ONCEMRK, 797 subjects were randomized and received at least 1 dose of either raltegravir 1200 mg once daily or raltegravir 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 797 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years (range 18-84), 15% female, 41% non-white, 3% had hepatitis B and/or C virus co-infection, 13% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, and 13% had CD4+ cell count less than 200 cells per mm3; the frequencies of these baseline characteristics were similar between treatment groups.

Table 17 shows the virologic outcomes in both studies. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up.

In the ONCEMRK trial, Isentress HD 1200 mg (2 × 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels >100,000 copies/mL and demographic groups (including age, gender, race, ethnicity and region), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).

Consistent efficacy in subjects receiving Isentress HD 1200 mg (2 × 600 mg) once daily was observed across HIV subtypes with 88.4% (296/335) and 90.2% (175/194) of subjects with B and non-B subtypes respectively, achieving HIV RNA <40 copies/mL at week 48 (Snapshot approach).

Treatment-Experienced Adult Subjects

BENCHMRK 1 and BENCHMRK 2 are Phase 3 studies to evaluate the safety and antiretroviral activity of Isentress 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-1-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.

Table 18 shows the demographic characteristics of subjects in the group receiving Isentress 400 mg twice daily and subjects in the placebo group.

Table 19 compares the characteristics of optimized background therapy at baseline in the group receiving Isentress 400 mg twice daily and subjects in the control group.

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of Isentress 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 20.

The mean changes in CD4 count from baseline were 118 cells/mm3 in the group receiving Isentress 400 mg twice daily and 47 cells/mm3 for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving Isentress 400 mg twice daily and 5% of the control group.

Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 21.

Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir

The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA <50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for >3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with Isentress 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.

Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to Isentress versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the Isentress group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.

Pediatric Subjects

2 to 18 Years of Age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of Isentress [see Dosage and Administration (2.3)].

These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).

4 Weeks to Less Than 2 Years of Age

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.

The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm3 (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 subjects were completely treatment naïve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of subjects greater than 6 months of age had received two or more antiretrovirals.

Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.

At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm3 (7.5%).

At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm3 (7.8%).

Isentress tablets 400 mg are pink, oval-shaped, film-coated tablets with "227" on one side. They are supplied as follows:

Isentress HD tablets 600 mg are yellow, oval-shaped, film-coated tablets with Merck logo and "242" on one side and plain on the other side. They are supplied as follows:

Isentress tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score. They are supplied as follows:

Isentress tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side. They are supplied as follows:

Isentress for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as a kit with two 5 mL dosing syringes and two mixing cups. It is supplied as follows:

Storage and Handling

400 mg Film-coated Tablets, 600 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). See USP Controlled Room Temperature.

400 mg Film-coated Tablets, 600 mg Film-coated Tablets and Chewable Tablets

Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

For Oral Suspension

Store in the original container. Do not open foil packet until ready for use.

Contraindications

None

Cautions

Risk of immune reconstitution syndrome if used with HAART

Autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment

Concomitant medications known to increase risk of myopathy or rhabdomyolysis

Coadministration with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir

Drug rash with eosinophilia and systemic symptoms (DRESS) reported

Severe, potentially life-threatening and fatal skin reactions reported; skin reactions include cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis; immediately discontinue treatment if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely

Phenylketonurics: Chewable tablets contain phenylalanine, a component of aspartame