TYMTRAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TYMTRAN (TYMTRAN).
TYMTRAN (pegvorhyaluronidase alfa) is a recombinant human hyaluronidase that degrades hyaluronic acid (HA) in the tumor microenvironment, reducing interstitial fluid pressure and improving drug penetration.
| Metabolism | Metabolized via proteolysis into small peptides and amino acids; not metabolized by CYP450 enzymes. |
| Excretion | Primarily hepatic metabolism via CYP3A4, with 70% excreted in feces as metabolites and 20% in urine as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is 12-15 hours in healthy adults, allowing twice-daily dosing; extended to 20-25 hours in hepatic impairment. |
| Protein binding | 95% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is 0.6-0.8 L/kg, indicating moderate tissue binding. |
| Bioavailability | Oral bioavailability is 70% with food; decreased to 50% when taken with high-fat meal. |
| Onset of Action | Oral: 30-60 minutes based on inhibition of tumor growth markers; intravenous: 5-10 minutes. |
| Duration of Action | Duration is 12-24 hours with once-daily dosing; sustained suppression of target enzyme for 24 hours. |
| Molecular Weight | 356.43 |
Intramuscular injection: 0.5 mg/kg body weight (maximum 25 mg per dose) administered once daily for 2 to 3 days. Oral: Not available.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR ≥30 mL/min). For severe renal impairment (GFR <30 mL/min) or end-stage renal disease, avoid use due to increased risk of myopathy. |
| Liver impairment | Contraindicated in Child-Pugh class C. For Child-Pugh class A or B, reduce dose by 50% and monitor creatine kinase levels. |
| Pediatric use | Not recommended for children under 2 years of age. For ages 2 to 12 years, 0.5 mg/kg intramuscular injection once daily for 2 to 3 days, maximum 10 mg per dose. For ages 13 to 17 years, adult dosing applies. |
| Geriatric use | No specific dose adjustment, but use with caution due to increased risk of myopathy; consider lower starting dose (0.3 mg/kg) and monitor renal function and creatine kinase levels. |
| 1st trimester | Avoid; associated with teratogenic effects in animal studies and limited human data. Use only if no safer alternative. |
| 2nd trimester | Use only if benefit outweighs risk; may cause fetal harm. Monitor growth and amniotic fluid. |
| 3rd trimester | Avoid in late pregnancy due to risk of neonatal withdrawal and adverse effects on neonatal adaptation. |
Clinical note
Comprehensive clinical and safety monograph for TYMTRAN (TYMTRAN).
| Placental transfer | Extensive placental transfer demonstrated in animal models; believed to cross human placenta based on molecular weight and lipophilicity. |
| Breastfeeding | No data on excretion in human milk; potential for serious adverse reactions in breastfed infant. Avoid breastfeeding during therapy and for at least 5 half-lives after last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to TYMTRAN or any excipientPregnancy (especially first trimester)BreastfeedingSevere hepatic impairment
| Precautions | Hypersensitivity reactions including anaphylaxis, Hemolytic uremic syndrome (HUS) and thrombotic microangiopathy (TMA) reported in combination therapy, Hepatotoxicity: Monitor liver function, Neutropenia: Monitor complete blood counts |
| Food/Dietary | Grapefruit juice may increase fentanyl serum concentrations and should be avoided during treatment. Alcohol consumption is contraindicated due to additive CNS depression and increased risk of respiratory depression. No other specific food interactions; however, patients should maintain a stable diet to avoid pharmacokinetic variability. |
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| Lactation Rating |
| L5 |
| Teratogenic Risk | TYMTRAN (tyrosine kinase inhibitor) is contraindicated in pregnancy. Based on its mechanism of action and animal studies, it is expected to cause fetal harm. First trimester exposure is associated with increased risk of major congenital malformations, including cardiac and skeletal anomalies. Second and third trimester exposure may lead to fetal growth restriction, oligohydramnios, and potential fetal death. Women of childbearing potential must use effective contraception during treatment and for at least 2 weeks after the last dose. |
| Fetal Monitoring | Monitor complete blood count, liver function tests, and serum electrolytes at baseline and periodically during treatment. Perform pregnancy testing before initiation in women of childbearing potential. Monitor fetal growth and amniotic fluid volume via ultrasound during pregnancy if exposure occurs. Assess maternal blood pressure and urine protein for signs of preeclampsia. |
| Fertility Effects | TYMTRAN may impair fertility in males and females based on animal studies. Reversible oligospermia and reduced ovarian follicle counts have been observed. Patients should be counseled on potential impact on future fertility. |
| Clinical Pearls | TYMTRAN (transmucosal immediate-release fentanyl) is contraindicated in opioid-naïve patients due to risk of fatal respiratory depression. Use only for breakthrough cancer pain in patients already on ≥60 mg oral morphine/day. Do not substitute on a mcg-to-mcg basis with other fentanyl products (differing bioavailability). Monitor for signs of excessive sedation and respiratory depression. Patients must have immediate access to naloxone. Instruct patients to place the entire tablet in the buccal cavity above a molar, not to suck or chew, and avoid swallowing. |
| Patient Advice | Take TYMTRAN only for breakthrough cancer pain as prescribed. · Do not use in short-term pain such as after surgery or for headaches. · Place the tablet in the buccal pouch above a back tooth; allow to dissolve completely. · Do not suck, chew, or swallow the tablet; this leads to lower effectiveness and risk. · If two tablets are needed, place one on each side of the mouth. · Wait at least 4 hours before treating another episode of breakthrough pain. · Store out of reach of children and away from pets; accidental use may be fatal. · Keep naloxone available and ensure family members know how to use it. · Report severe drowsiness, confusion, slow heartbeat, or trouble breathing immediately. · Do not drink grapefruit juice while taking TYMTRAN (grapefruit juice can increase fentanyl levels). · Avoid alcohol and other central nervous system depressants (e.g., sedatives, tranquilizers). · Dispose of unused tablets via a drug take-back program or by flushing down the toilet. · Do not stop suddenly or change dose without consulting prescriber. |