Important Safety Information

Do not prescribe NITYR to patients allergic to nitisinone or any other ingredients.

Warnings and Precautions:

Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques:

·        Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine, which at levels above 500 micromol/L can result in ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia, intellectual disability and developmental delay or painful hyperkeratotic plaques on the soles and palms.

·        Do not adjust the NITYR dosage in order to lower the plasma tyrosine concentration.

·        Perform baseline ophthalmologic examination including slit-lamp examination prior to initiating treatment, and regularly during treatment. Reexamine patients if symptoms develop or tyrosine levels are > 500 micromol/L.

·        Perform a clinical laboratory assessment, including plasma tyrosine levels, in patients with an abrupt change in neurologic status.

Leukopenia and Severe Thrombocytopenia Patients can develop leukopenia and severe thrombocytopenia: monitor platelet and white blood cell counts.

Most Common Adverse Reactions: The most common adverse reactions (≥1%) reported in patients with HT-1 taking nitisinone in the clinical trials are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia.

Drug Interactions:

• Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3.

• Potential clinical impact of concomitant administration with CYP2C9 Substrates: Increased systemic exposure of co-administered drugs metabolized by CYP2C9. Intervention: reduce the dosage of the co-administered drugs metabolized by CYP2C9 by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs.

• Potential clinical impact of concomitant administration with OAT1/OAT3 Substrates: Increased exposure of these co-administered drugs; monitor for potential adverse reactions.

Use in Specific Populations:

Pregnancy: Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes.

Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NITYR and any potential adverse effects on the breastfed infant from NITYR or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of nitisinone have been established in pediatric patients for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use of NITYR in pediatric patients is supported by evidence from one open-label, uncontrolled clinical study conducted with another oral formulation of nitisinone in 207 patients with HT-1 ages 0 to 22 years (median age 9 months)

Geriatric Use: Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

For more detailed information, please refer to the full Prescribing Information.

To report SUSPECTED ADVERSE REACTIONS contact Cycle Pharmaceuticals at 1-855-831-5413, or the FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch.

*NITYR® (nitisinone) Tablets is approved in the USA, Australia, New Zealand, the Kingdom of Saudi Arabia, the Kingdom of Morocco and Israel in 2, 5 and 10 mg strengths and in the EU, Egypt and Chile in 10 mg strength. Cycle Pharmaceuticals’ nitisinone products are also approved under a different name, NITISINONE TABLETS, in Canada in 2, 5, and 10 mg strengths. Registration conditions differ internationally.

Indications

SAJAZIR^TM  (icatibant) injection is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.

Important Safety Information

Warnings and Precautions

Laryngeal Attacks. Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with SAJAZIR.

Adverse Reactions

The most commonly reported adverse reactions were injection site reactions, which occurred in almost all patients (97%) in clinical trials. Other common adverse reactions occurring in greater than 1% of patients included pyrexia (4%), transaminase increase (4%), dizziness (3%), and rash.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of icatibant: urticaria.

Drug Interactions:

ACE Inhibitors. Icatibant is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where icatibant may attenuate the antihypertensive effect of ACE inhibitors. Clinical trials to date have excluded subjects taking ACE inhibitors.

Use in Specific Populations

Pregnancy: Available data from published literature and the pharmacovigilance database with icatibant use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for icatibant and any potential adverse effects on the breastfed child from icatibant or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use: Elderly patients are likely to have increased systemic exposure to icatibant injection compared to younger (18-45 years) patients. No dose adjustment is recommended.

For more detailed information, please refer to the full Prescribing Information

To report SUSPECTED ADVERSE REACTIONS contact Cycle Pharmaceuticals at 1-800-836-4380, or the FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch.

References

1. SAJAZIR™ (icatibant) Injection. Prescribing Information. Cycle Pharmaceuticals Limited.
2. Maurer M, et al. Allergy. 2018;73(8):1575–1596.
3. Zuraw BL, et al. J Allergy Clin Immunol Pract. 2013;1(5):458–467.
4. El-Shanawany T. Hereditary Angioedema. British Society for Immunology. https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/hereditary-angioedema (accessed October 2021).

INDICATION
JAVYGTOR is indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). JAVYGTOR is to be used in conjunction with a Phe-restricted diet.

IMPORTANT SAFETY INFORMATION
Treatment with JAVYGTOR should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with JAVYGTOR should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction. Prolonged exposure to elevated blood Phe levels can result in severe neurologic damage in PKU patients.

During treatment with JAVYGTOR, monitor blood Phe levels frequently to ensure adequate blood Phe level control, especially in pediatric patients. Also, active management of dietary Phe intake is required to ensure adequate Phe control and nutritional balance. Biochemical response to JAVYGTOR treatment should be determined through a therapeutic trial.

Patients should be advised to notify their physicians in cases of overdose.

WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions Including Anaphylaxis: JAVYGTOR is not recommended in patients with a history of anaphylaxis to SAPROPTERIN DIHYDROCHLORIDE. Hypersensitivity reactions, including anaphylaxis and rash, have occurred. Signs of anaphylaxis include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash. Discontinue JAVYGTOR treatment in patients who experience anaphylaxis, and initiate appropriate medical treatment. Continue dietary protein and Phe restrictions in patients who experience anaphylaxis.
• Upper Gastrointestinal Mucosal Inflammation: Gastrointestinal (GI) adverse reactions suggestive of upper GI mucosal inflammation have been reported with JAVYGTOR. Serious adverse reactions included esophagitis and gastritis. If left untreated, these could lead to severe sequelae including esophageal stricture, esophageal ulcer, gastric ulcer, and bleeding, and such complications have been reported in patients receiving SAPROPTERIN DIHYDROCHLORIDE. Monitor patients for signs and symptoms of upper GI mucosal inflammation.
• Hypophenylalaninemia: Some patients receiving SAPROPTERIN DIHYDROCHLORIDE have experienced hypophenylalaninemia (low blood Phe) during treatment. Children younger than 7 years old treated with JAVYGTOR doses of 20 mg/kg per day are at an increased risk for low levels of blood Phe compared with older patients.
• Monitoring Blood Phe Levels During Treatment: Prolonged elevations of blood Phe levels in patients with PKU can result in severe neurologic damage, including severe intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities. Conversely, prolonged levels of blood Phe that are too low have been associated with catabolism and endogenous protein breakdown, which has been associated with adverse developmental outcomes. Active management of dietary Phe intake while taking sapropterin dihydrochloride is required to ensure adequate Phe control and nutritional balance. Monitor blood Phe levels during treatment to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population.
• Lack of Biochemical Response to JAVYGTOR: Not all patients with PKU respond to treatment with JAVYGTOR. Biochemical response to JAVYGTOR treatment cannot generally be pre-determined by laboratory testing (e.g., molecular testing), and should be determined through a therapeutic trial (evaluation) of JAVYGTOR response.
• Interactions with Levodopa: There have been reports of interactions with levodopa causing seizures, exacerbation of seizures, over-stimulation, and irritability. Monitor patients who are receiving levodopa for a change in neurologic status during treatment with JAVYGTOR.#
• Hyperactivity: There have been post-marketing reports of hyperactivity with administration of SAPROPTERIN DIHYDROCHLORIDE. Monitor patients for hyperactivity.

ADVERSE REACTIONS

• Most common: The most common adverse reactions (incidence ≥4%) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The following adverse reactions have been reported during post-approval use of sapropterin dihydrochloride:

• Hypersensitivity reactions including anaphylaxis and rash. Most hypersensitivity reactions occurred within several days of initiating treatment;
• Gastrointestinal reactions: esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting;
• Hyperactivity

DRUG INTERACTIONS

• Levodopa – JAVYGTOR may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported post-marketing in patients receiving sapropterin and levodopa concomitantly for a non-PKU indication. Monitor patients for a change in neurologic status.
• Inhibitors of Folate Synthesis – Drugs that inhibit folate synthesis may decrease the bioavailability of endogenous BH4 by inhibiting the enzyme dihydrofolate reductase, which is involved in the recycling (regeneration) of BH4. This reduction in net BH4 levels may increase Phe levels. Frequently monitor blood Phe levels when co-administering JAVYGTOR with medications known to inhibit folate synthesis, such as methotrexate, valproic acid, phenobarbital, trimethoprim.
• Drugs Affecting Nitric Oxide-Mediated Vasorelaxation – Both JAVYGTOR and PDE- 5 inhibitors (such as sildenafil, vardenafil, or tadalafil) may induce vasorelaxation. A reduction in blood pressure could occur. Monitor patients for hypotension when co-administering JAVYGTOR with medications known to affect nitric oxide–mediated vasorelaxation such as PDE-5 inhibitors.

USE IN SPECIFIC POPULATIONS

• Pregnancy: There are no well-controlled clinical studies of Sapropterin Dihydrochloride in pregnant women.
• Lactation: There are insufficient data to assess the presence of sapropterin in human milk and no data on the effects on milk production.
• Pediatric Use: Pediatric patients with PKU, ages 1 month to 16 years, have been treated with sapropterin dihydrochloride in clinical trials. The efficacy and safety of sapropterin dihydrochloride have not been established in neonates.
• Geriatric Use: Clinical studies of sapropterin dihydrochloride in patients with PKU did not include patients aged 65 years and older. It is not known whether these patients respond differently than younger patients.
  For more detailed information, please refer to the full Prescribing Information at: www.JAVYGTOR.com/PI

To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or by email: medinfo@drreddys.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Indications

TASCENSO ODT is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older.

Contraindications

• Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure with hospitalization, or Class III/IV heart failure.
• Patients with a history or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• Patients with a baseline QTc interval ≥ 500 msec.
• Patients with cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs.
• Patients who had a hypersensitivity to fingolimod or any excipients in TASCENSO ODT.
• Concomitant use with other products containing fingolimod.

Important Safety Information

Warnings and Precautions:

Due to a risk for bradyarrhythmia and AV blocks patients should be monitored during TASCENSO ODT treatment initiation. TASCENSO ODT may increase blood pressure, risk of infections and may cause fetal harm. Cases of Progressive Multifocal Leukoencephalopathy and of clinically significant liver injury have occurred in patients treated with fingolimod in the postmarketing setting. TASCENSO ODT increases risk of macular edema. Rare cases of Posterior Reversible Encephalopathy Syndrome in adults have been reported with fingolimod. Fingolimod can have respiratory effects. Severe increase in disability accompanied by multiple new lesions on MRI has been reported following discontinuation of fingolimod. MS relapses with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after discontinuation. The risk of basal cell carcinoma and melanoma is increased in patients treated with fingolimod. Cases of lymphoma have been reported in patients receiving fingolimod. The reporting rate of non-Hodgkin lymphoma with fingolimod is greater than that expected in the general population. Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts for up to 2 months following the last dose. Hypersensitivity reactions including rash, urticaria, and angioedema have been reported with fingolimod. Cases of seizures, including status epilepticus, have been reported with the use of fingolimod.

Adverse Reactions:

In clinical trials, the most common adverse reactions (incidence ≥ 10% and >placebo) are headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity.

Drug Interactions:

Patients on QT prolonging drugs with a known risk of torsades de pointes should be monitored during initiation of treatment with TASCENSO ODT. Monitor patients during use of systemic ketoconazole. Use of live attenuated vaccines during, and for 2 months after stopping TASCENSO ODT, should be avoided.

For more detailed information, please refer to the full Prescribing Information at www.tascenso.com/PI.

To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd at 1-888-533-1625 or the FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch.