What happens if I overdose Romisan?
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include diarrhea.
Proper storage of Romisan:
Romisan is usually handled and stored by a health care provider. If you are using Romisan at home, store Romisan as directed by your pharmacist or health care provider. Keep Romisan out of the reach of children and away from pets.
Overdose of Romisan in details
In U.S. phase 1 trials, single doses of up to 345 mg/m2 of Romisan were administered to patients with various cancers. Single doses of up to 750 mg/m2 of Romisan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of Romisan hydrochloride injection. Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.
What should I avoid while taking Romisan?
Avoid using a laxative or stool softener during treatment with Romisan.
Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.
Do not receive a "live" vaccine while using Romisan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.
Romisan may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.
Romisan can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.
Romisan warnings
Diarrhea and Cholinergic Reactions
Early diarrhea (occurring during or shortly after infusion of Romisan) is usually transient and infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Bradycardia may also occur. Early diarrhea and other cholinergic symptoms may be prevented or treated. Consider prophylactic or therapeutic administration of 0.25 mg to 1 mg of intravenous or subcutaneous atropine (unless clinically contraindicated). These symptoms are expected to occur more frequently with higher Romisan doses.
Late diarrhea (generally occurring more than 24 hours after administration of Romisan) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Grade 3–4 late diarrhea occurred in 23–31% of patients receiving weekly dosing. In the clinical studies, the median time to the onset of late diarrhea was 5 days with 3-week dosing and 11 days with weekly dosing. Late diarrhea can be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients should have loperamide readily available to begin treatment for late diarrhea. Begin loperamide at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normal. One dosage regimen for loperamide is 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus. During the night, the patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. Use antibiotic support for ileus, fever, or severe neutropenia. Subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without anti-diarrhea medication. Patients must not be treated with Romisan until resolution of the bowel obstruction. If grade 2, 3, or 4 late diarrhea recurs, subsequent doses of Romisan should be decreased.
Avoid diuretics or laxatives in patients with diarrhea.
Myelosuppression
Deaths due to sepsis following severe neutropenia have been reported in patients treated with Romisan. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. Manage febrile neutropenia promptly with antibiotic support. Hold Romisan if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After recovery to an absolute neutrophil count ≥1000/mm3, subsequent doses of Romisan should be reduced.
When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of Romisan. Based on sparse available data, the concurrent administration of Romisan with irradiation is not recommended.
Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with Romisan.
Patients With Reduced UGT1A1 Activity
Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Romisan treatment.
In a study of 66 patients who received single-agent Romisan (350 mg/m2 once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).
In a prospective study (n=250) to investigate the role of UGT1A1*28 polymorphism in the development of toxicity in patients treated with Romisan (180 mg/m2) in combination with infusional 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 4.5%, and in patients heterozygous for this allele the incidence was 5.3%. Grade 4 neutropenia was observed in 1.8% of patients homozygous for the wild-type allele.
In another study in which 109 patients were treated with Romisan (100–125 mg/m2) in combination with bolus 5-FU/LV, the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 18.2%, and in patients heterozygous for this allele the incidence was 11.1%. Grade 4 neutropenia was observed in 6.8% of patients homozygous for the wild-type allele.
When administered in combination with other agents or as a single-agent, a reduction in the starting dose by at least one level of Romisan should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment.
UGT1A1 Testing
A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.
Hypersensitivity
Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed. Discontinue Romisan if anaphylactic reaction occurs.
Renal Impairment/Renal Failure
Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.
Pulmonary Toxicity
Interstitial Pulmonary Disease (IPD)-like events, including fatalities, have occurred in patients receiving Romisan (in combination and as monotherapy). Risk factors include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during Romisan therapy. In Japanese studies, a reticulonodular pattern on chest x-ray was observed in a small percentage of patients. New or progressive, dyspnea, cough, and fever should prompt interruption of chemotherapy, pending diagnostic evaluation. If IPD is diagnosed, Romisan and other chemotherapy should be discontinued and appropriate treatment instituted as needed.
Toxicity of the 5 Day Regimen
Outside of a well-designed clinical study, Romisan Injection should not be used in combination with a regimen of 5-FU/LV administered for 4–5 consecutive days every 4 weeks because of reports of increased toxicity, including toxic deaths. Romisan should be used as recommended in Table 2.
Increased Toxicity in Patients with Performance Status 2
In patients receiving either Romisan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.
Embryofetal Toxicity
Romisan can cause fetal harm when administered to a pregnant woman. Romisan was embryotoxic in rats and rabbits at doses significantly lower than those administered to humans on a mg/m2 basis. In rats, at exposures approximately 0.2 times those achieved in humans at the 125 mg/m2 dose, Romisan was embryotoxic and resulted in decreased learning ability and female fetal body weight in surviving pups; the drug was teratogenic at lower exposures (approximately 0.025 times the AUC in humans at the 125 mg/m2 dose). There are no adequate and well-controlled studies of Romisan in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Romisan.
Patients with Hepatic Impairment
The use of Romisan in patients with significant hepatic impairment has not been established. In clinical trials of either dosing schedule, Romisan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001).
What should I discuss with my healthcare provider before taking Romisan?
Some medical conditions may interact with Romisan. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
- if you are pregnant, planning to become pregnant, or are breast-feeding
- if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
- if you have allergies to medicines, foods, or other substances
- if you have liver disease; a blood disorder; bone marrow depression; diabetes or high blood sugar; kidney or lung disease; or herpes zoster, varicella, or another infection; or you cannot tolerate fructose
- if you have recently received or will be receiving a live vaccine (eg, measles, mumps)
- if you have recently had or will be having dental procedures or radiation therapy
Some MEDICINES MAY INTERACT with Romisan. Tell your health care provider if you are taking any other medicines, especially any of the following:
- Other antineoplastic agents, dexamethasone, diuretics (eg, furosemide), ketoconazole, or prochlorperazine because they may increase the risk of Romisan's side effects
- Carbamazepine, hydantoins (eg, phenytoin), phenobarbital, rifabutin, rifampin, or St. John's wort because they may decrease Romisan's effectiveness
This may not be a complete list of all interactions that may occur. Ask your health care provider if Romisan may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Romisan precautions
Romisan should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Romisan can induce diarrhea. The diarrhea is of 2 types. Both forms of diarrhea may be severe. Early diarrhea occurs during or shortly after infusion of Romisan and it may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and intestinal peristalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine. Late diarrhea occurs >24 hrs after administration of Romisan and can be prolonged, it may lead to dehydration and electrolyte imbalance and can be life-threatening. Late diarrhea should be treated promptly with loperamide; patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever or neutropenia. Administration of the Romisan should be interrupted and subsequent doses reduced if severe diarrhea occurs.
Care of IV Site: Romisan has to be administered by IV infusion. Care should be taken to avoid extravasations and the infusion site should be monitored for signs of inflammation.
Premedication: Romisan is emetogenic. It is recommended that patients receive antiemetic premedication. Antiemetic premedication should be given at least 30 min before administering Romisan.
Cholinergic symptoms are likely to occur in patients receiving higher doses of Romisan. In such patients, prophylactic or therapeutic administration of atropine at a dose of 0.25-1 mg by IV or SC route should be considered.
Patients at Particular Risk: Higher rates of hospitalization, neutropenic fever, thromboembolism, first cycle discontinuation and early deaths were observed in patients with performance status 2 than in patients with performance status 0-1.
Patients with Impaired Liver Function: The use of Romisan in patients with significant hepatic failure has not been established. The likehood of developing first cycle grade 3 or 4 neutropenia is high in patients having elevated baseline serum bilirubin levels (1-2 mg/dL) with weekly Romisan and 5-FU/LV regimen.
Patients with Impaired Kidney Function: The effect of renal impairment on Romisan pharmacokinetics has not been evaluated. However, rare cases of renal impairment and acute renal failure have been identified, usually in patients whose volume is depleted from severe vomiting and/or diarrhea.
Use in pregnancy & lactation: Safety and efficacy of Romisan in pregnant and lactating women is not well established.
Use in children: The safety and efficacy of Romisan is not established in pediatric patients.
Use in the
Elderly: Patients >65 years should be closely monitored because of a greater risk of late diarrhea.
What happens if I miss a dose of Romisan?
Call your doctor for instructions if you miss an appointment for your Romisan injection.
References
- DailyMed. "OMEPRAZOLE MAGNESIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- DrugBank. "irinotecan". http://www.drugbank.ca/drugs/DB00762 (accessed September 17, 2018).
- DrugBank. "omeprazole". http://www.drugbank.ca/drugs/DB00338 (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
