HELIDAC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HELIDAC (HELIDAC).
HELIDAC (vorinostat) is a histone deacetylase (HDAC) inhibitor. It inhibits the enzymatic activity of HDACs, leading to increased acetylation of histone proteins and transcription factors, which alters gene expression and induces cell cycle arrest, differentiation, and apoptosis in cancer cells.
| Metabolism | Primarily hepatic metabolism via glucuronidation (UGT2B17) and oxidation (CYP3A4, CYP2A6, CYP2D6 minor). The major metabolite is vorinostat glucuronide, which is pharmacologically inactive. Approximately 50% of the dose is excreted as unchanged drug and metabolites in urine and feces. |
| Excretion | HELIDAC (bismuth subsalicylate) is primarily eliminated as bismuth via feces (99%): approximately 90% as unchanged bismuth subsalicylate and 10% as bismuth oxychloride. Renal excretion of bismuth is minimal (<0.5% of dose), though salicylate component is renally excreted. Biliary excretion accounts for <1% of bismuth. |
| Half-life | Terminal elimination half-life of bismuth is approximately 5 days (range 3-11 days) due to slow clearance from tissues; salicylate half-life is 2-3 hours. Clinical context: Bismuth accumulates with repeated dosing, reaching steady-state after 2-3 weeks. |
| Protein binding | Bismuth is extensively protein-bound (>95%) to albumin and alpha-2-macroglobulin; salicylate is 80-90% bound to albumin. |
| Volume of Distribution | Vd for bismuth is approximately 0.7-1.2 L/kg (range 0.5-1.5 L/kg), indicating distribution into total body water with some tissue binding. Clinical meaning: Large Vd suggests significant extravascular distribution, explaining slow elimination. |
| Bioavailability | Oral bioavailability of bismuth from subsalicylate is <1% (range 0.2-0.7%) due to poor absorption; salicylate component is well absorbed (~80-90%) but rapidly metabolized. No parenteral route available. |
| Onset of Action | Oral: Onset of anti-diarrheal effect occurs within 1-2 hours; antibacterial effect against H. pylori requires 2-4 weeks of combination therapy. Topical (oral suspension/gel): Onset for mucosal coating is immediate. |
| Duration of Action | Anti-diarrheal effect lasts 4-8 hours after single oral dose. H. pylori eradication requires 14-day triple therapy regimen; mucosal protection persists ~2-3 hours after oral dosing. |
Helidac (bismuth subsalicylate/metronidazole/tetracycline) is not commercially available; individual components are used. For Helicobacter pylori eradication: bismuth subsalicylate 524 mg orally four times daily, metronidazole 250 mg orally four times daily, tetracycline 500 mg orally four times daily, plus a proton pump inhibitor (e.g., omeprazole 20 mg twice daily) for 10-14 days.
| Dosage form | TABLET, CHEWABLE, TABLET, CAPSULE |
| Renal impairment | Metronidazole: No adjustment. Tetracycline: Avoid in severe renal impairment (CrCl <30 mL/min); accumulation may occur. Bismuth subsalicylate: Avoid in renal impairment due to salicylate accumulation. |
| Liver impairment | Metronidazole: Reduce dose by 50% in severe hepatic impairment (Child-Pugh C). Tetracycline: No specific adjustment. Bismuth subsalicylate: Caution in hepatic impairment due to salicylate. |
| Pediatric use | Not typically approved for H. pylori eradication in children. If used: Bismuth subsalicylate 8-16 mg/kg/day in 4 divided doses (max 4.2 g/day), metronidazole 15-20 mg/kg/day in 3 divided doses (max 2 g/day), tetracycline not recommended under 8 years (use amoxicillin instead). |
| Geriatric use | Use with caution due to increased risk of renal impairment, drug interactions (warfarin, hypoglycemics), and metronidazole neurotoxicity. Consider lower doses of tetracycline (monitor renal function) and bismuth (risk of salicylate toxicity). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for HELIDAC (HELIDAC).
| Breastfeeding | Contraindicated during breastfeeding. Tetracycline excreted in milk, causing dental staining and bone growth inhibition in infants. Metronidazole: significant transfer; M/P ratio ~0.96, may cause diarrhea, candidiasis. Bismuth subsalicylate: salicylate component passes into milk, risk of Reye's syndrome. Avoid nursing for at least 48 hours after last dose. |
| Teratogenic Risk | Helidac (bismuth subsalicylate, metronidazole, tetracycline) is contraindicated in pregnancy. Tetracycline causes fetal skeletal and dental anomalies, metronidazole is carcinogenic in animal studies, and bismuth subsalicylate may cause Reye's syndrome. First trimester: high risk of congenital malformations. Second trimester: continued risk of tetracycline discoloration. Third trimester: risk of Reye's syndrome and fetal harm. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Severe hypersensitivity to vorinostat or any component of the formulation.","Pregnancy (can cause fetal harm based on animal data; effective contraception required)."]
| Precautions | ["Pulmonary embolism and deep vein thrombosis have been reported; monitor for thromboembolic events.","Hematologic toxicity (thrombocytopenia, anemia, neutropenia) – monitor blood counts regularly.","QT prolongation – caution in patients with electrolyte abnormalities, bradyarrhythmias, or concomitant QT-prolonging drugs.","Gastrointestinal toxicity (nausea, vomiting, diarrhea) – may require antiemetic and antidiarrheal therapy.","Hyperglycemia – monitor serum glucose, especially in diabetic patients.","Severe hepatic impairment – dose reduction recommended; monitor liver enzymes."] |
| Food/Dietary | Avoid dairy products (milk, cheese, yogurt), antacids, or iron supplements within 2-3 hours of taking tetracycline as they reduce absorption. Avoid alcohol during metronidazole therapy and for 48 hours after completion. Take with food to minimize gastrointestinal side effects. |
Loading safety data…
| Fetal Monitoring | Monitor fetal growth and development via ultrasound, assess for skeletal anomalies (tetracycline-related). Maternal monitoring: renal function, hepatic function, CBC due to metronidazole. Watch for signs of Reye's syndrome (vomiting, lethargy, hepatomegaly) in both mother and neonate if exposed. |
| Fertility Effects | No direct studies on human fertility. Metronidazole may affect spermatogenesis in animal studies. Tetracycline can cause reversible impairment of sperm motility. Biopsy studies show no long-term fertility effects in women. Advise discontinuation before planned conception due to teratogenicity. |
| Clinical Pearls | HELIDAC (bismuth subsalicylate, metronidazole, tetracycline) is a three-in-one combination therapy for H. pylori eradication. Avoid use in patients with aspirin allergy due to bismuth subsalicylate. Tetracycline component contraindicated in pregnancy and children under 8 years. Regimen requires strict adherence to 14-day course to prevent resistance. Administer with meals to reduce GI upset. |
| Patient Advice | Take all three medications together four times daily for a full 14 days, even if symptoms improve. · Do not take this medication if you are pregnant or breastfeeding, or if you have a history of aspirin allergy. · Avoid alcohol during treatment and for at least 48 hours after stopping metronidazole to prevent disulfiram-like reaction. · May cause dark stools or tongue discoloration due to bismuth; this is harmless. · Take tetracycline with a full glass of water and avoid dairy products, antacids, or iron supplements within 2-3 hours of dosing. |