Drug Interaction Report

Ifosfamide may cause central nervous system side effects such as drowsiness, confusion, hallucinations, blurred vision, abnormal behavior, abnormal muscle movements, seizures, and even coma in some cases. Combining it with other medications that can also affect the nervous system such as LORazepam may increase the risk and/or severity of these effects. Talk to your doctor if you have any questions or concerns. Your doctor may be able to prescribe alternatives that do not interact, or you may need a dose adjustment or more frequent monitoring to safely use both medications. You should avoid or limit the use of alcohol while being treated with these medications. Also avoid driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until you know how the medications affect you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Alcohol can increase the nervous system side effects of LORazepam such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with LORazepam. Do not use more than the recommended dose of LORazepam, and avoid activities requiring mental alertness such as driving or operating hazardous machinery until you know how the medication affects you. Talk to your doctor or pharmacist if you have any questions or concerns.

Do not consume grapefruit or grapefruit juice while you are receiving treatment with ifosfamide, as this may decrease the anticancer effects of ifosfamide and may increase its adverse effects on your nervous system and your kidneys. Do not use alcohol while you are receiving treatment with ifosfamide. This may increase nervous system side effects such as somnolence, dizziness, confusion, difficulty concentrating, and impairment of thinking and judgment; and may also increase nausea and vomiting. Talk to your doctor or pharmacist if you have questions on how to take this or other medications you are prescribed. Also, avoid activities requiring mental alertness such as driving or operating hazardous machinery until you know how the medication affects you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medication without first talking to your doctor.

The use of benzodiazepines with alcohol is not recommended. Patients with acute alcohol intoxication exhibit depressed vital signs. The central nervous system depressant effects of benzodiazepines may be additive with those of alcohol, and severe respiratory depression and death may occur. Therapy with benzodiazepines should be administered cautiously in patients who might be prone to acute alcohol intake.

Benzodiazepines should not be administered by injection to patients in shock or coma. The hypnotic and hypotensive effects of these agents may be prolonged and intensified in such patients.

Benzodiazepines may cause respiratory depression and apnea, usually when given in high dosages and/or by intravenous administration. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with benzodiazepines should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are particularly important, and equipment for resuscitation should be immediately available if the parenteral route is used. Benzodiazepines, especially injectable formulations, should generally be avoided in patients with sleep apnea, severe respiratory insufficiency, or hypoxia.

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe or fatal infections. Patients should be instructed to immediately report any signs or symptoms suggesting bone marrow suppression such as fever, sore throat, local infection, or bleeding. Complete blood counts should be obtained prior to administration of each dose and unless clinically essential, ifosfamide should be withheld if white blood cell counts falls below 1,500 to 2,000/mm3 and/or platelet counts falls below 50,000/mm3. Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe or fatal infections. Patients should be instructed to immediately report any signs or symptoms suggesting bone marrow suppression such as fever, sore throat, local infection, or bleeding. Complete blood counts should be obtained prior to administration of each dose and unless clinically essential, ifosfamide should be withheld if white blood cell counts falls below 1,500 to 2,000/mm3 and/or platelet counts falls below 50,000/mm3. Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Benzodiazepines have the potential to cause dependence and abuse. Tolerance as well as physical and psychological dependence can develop, particularly after prolonged use and/or excessive dosages. However, abrupt cessation following continual use of as few as 6 weeks at therapeutic levels has occasionally precipitated withdrawal symptoms. Addiction- prone individuals, such as those with a history of alcohol or substance abuse, should be under careful surveillance when treated with benzodiazepines. It may be prudent to refrain from dispensing large quantities of medication to these patients. After prolonged use or if dependency is suspected, withdrawal of benzodiazepine therapy should be undertaken gradually using a dosage- tapering schedule. If withdrawal symptoms occur, temporary reinstitution of benzodiazepines may be necessary.

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe or fatal infections. Patients should be instructed to immediately report any signs or symptoms suggesting bone marrow suppression such as fever, sore throat, local infection, or bleeding. Complete blood counts should be obtained prior to administration of each dose and unless clinically essential, ifosfamide should be withheld if white blood cell counts falls below 1,500 to 2,000/mm3 and/or platelet counts falls below 50,000/mm3. Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

The manufacturers consider the use of benzodiazepines to be contraindicated in patients with acute angle-closure glaucoma or untreated open-angle glaucoma. These agents do not possess anticholinergic activity but have very rarely been associated with increased intraocular pressure.

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe or fatal infections. Patients should be instructed to immediately report any signs or symptoms suggesting bone marrow suppression such as fever, sore throat, local infection, or bleeding. Complete blood counts should be obtained prior to administration of each dose and unless clinically essential, ifosfamide should be withheld if white blood cell counts falls below 1,500 to 2,000/mm3 and/or platelet counts falls below 50,000/mm3. Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Because of their cytotoxic effects on rapidly proliferating tissues, antineoplastic agents frequently can, to varying extent, induce myelosuppression. The use of these drugs may be contraindicated in patients with known infectious diseases. All patients should be instructed to immediately report any signs or symptoms suggesting infection such as fever, sore throat, or local infection during antineoplastic therapy. Close clinical monitoring of hematopoietic function is recommended.

Benzodiazepines are metabolized by the liver, and the metabolites are excreted in the urine. Chlordiazepoxide, clorazepate, diazepam, flurazepam and quazepam undergo oxidative N-dealkylation to active metabolites that are substantially longer-acting than the parent compound. These metabolites then undergo further biotransformation to pharmacologically inactive products before excretion by the kidney. Therapy with benzodiazepines should be administered cautiously at lower initial dosages in patients with impaired renal and/or hepatic function. Agents that are converted to weakly active, short-acting, or inactive metabolites may be preferable in hepatic impairment. Lorazepam, oxazepam and temazepam are conjugated to inactive metabolites, while alprazolam, estazolam and triazolam undergo hydroxylation to weakly active or inactive metabolites.

Parenteral medications formulated in multidose vials often contain benzyl alcohol as a preservative. Their use is considered by drug manufacturers to be contraindicated in neonates, particularly premature infants and infants of low birth weight. When used in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions, benzyl alcohol has been associated with fatalities and severe respiratory and metabolic complications in low-birth-weight premature infants. Thus, single-dose formulations should always be used in infants whenever possible. However, many experts feel that, in the absence of benzyl alcohol-free equivalents, the amount of the preservative present in these formulations should not necessarily preclude their use if they are clearly indicated. The American Academy of Pediatrics considers benzyl alcohol in low doses (such as when used as a preservative in some medications) to be safe for newborns. However, the administration of high dosages of these medications must take into account the total amount of benzyl alcohol administered. The level at which toxicity may occur is unknown.

Benzodiazepines may cause respiratory depression and apnea, usually when given in high dosages and/or by intravenous administration. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with benzodiazepines should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are particularly important, and equipment for resuscitation should be immediately available if the parenteral route is used. Benzodiazepines, especially injectable formulations, should generally be avoided in patients with sleep apnea, severe respiratory insufficiency, or hypoxia.

Benzodiazepines are metabolized by the liver, and the metabolites are excreted in the urine. Chlordiazepoxide, clorazepate, diazepam, flurazepam and quazepam undergo oxidative N-dealkylation to active metabolites that are substantially longer-acting than the parent compound. These metabolites then undergo further biotransformation to pharmacologically inactive products before excretion by the kidney. Therapy with benzodiazepines should be administered cautiously at lower initial dosages in patients with impaired renal and/or hepatic function. Agents that are converted to weakly active, short-acting, or inactive metabolites may be preferable in hepatic impairment. Lorazepam, oxazepam and temazepam are conjugated to inactive metabolites, while alprazolam, estazolam and triazolam undergo hydroxylation to weakly active or inactive metabolites.

Benzodiazepines may cause respiratory depression and apnea, usually when given in high dosages and/or by intravenous administration. However, some patients may be susceptible at commonly used dosages, including the elderly, debilitated or severely ill patients, those receiving other CNS depressants, and those with limited ventilatory reserve, chronic pulmonary insufficiency or other respiratory disorders. Therapy with benzodiazepines should be administered cautiously in these patients. Appropriate monitoring and individualization of dosage are particularly important, and equipment for resuscitation should be immediately available if the parenteral route is used. Benzodiazepines, especially injectable formulations, should generally be avoided in patients with sleep apnea, severe respiratory insufficiency, or hypoxia.

The use of benzodiazepines in patients with seizure disorders may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). Appropriate anticonvulsant medication might need to be initiated or the dosage increased. Abrupt cessation of benzodiazepine therapy may precipitate seizures and other withdrawal symptoms, particularly after prolonged use and/or excessive dosages. Status epilepticus may occur in patients with a history of seizures withdrawn rapidly from benzodiazepine therapy. Following chronic administration, cessation of benzodiazepine therapy should occur gradually with incrementally reduced dosages. Patients should be advised not to discontinue medication without first consulting with the physician.

Benzodiazepines should not be administered by injection to patients in shock or coma. The hypnotic and hypotensive effects of these agents may be prolonged and intensified in such patients.

Benzodiazepines depress the central nervous system and may cause or exacerbate mental depression and cause suicidal behavior and ideation. Episodes of mania and hypomania have also been reported in depressed patients treated with some of these agents. Therapy with benzodiazepines should be administered cautiously in patients with a history of depression or other psychiatric disorders. Patients should be monitored for any changes in mood or behavior. It may be prudent to refrain from dispensing large quantities of medication to these patients.

The manufacturer recommends the use of caution when prescribing lorazepam for prolonged periods in patients with upper gastrointestinal disease, especially in the elderly. The appearance or worsening of upper gastrointestinal symptoms should be monitored.

Paradoxical reactions, including excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams, have been reported with the use of benzodiazepines in psychiatric patients and pediatric patients with hyperactive aggressive disorders. Such patients should be monitored for signs of paradoxical stimulation during therapy with benzodiazepines. The manufacturers do not recommend the use of benzodiazepines for the treatment of psychosis.

Ifosfamide is metabolized by the liver to a biologically active form. Metabolic activation and therapeutic activity may be altered in patients with hepatic impairment. Therapy with ifosfamide should be administered cautiously in patients with compromised hepatic function. Clinical monitoring of hepatic function is recommended.

The plasma half-lives of benzodiazepines may be prolonged in obese patients, presumably due to increased distribution into fat. Marked increases in distribution (> 100%) have been reported for diazepam and midazolam, and moderate increases (25% to 100%) for alprazolam, lorazepam, and oxazepam. Therapy with benzodiazepines should be administered cautiously in obese patients, with careful monitoring of CNS status. Longer dosing intervals may be appropriate. When dosing by weight, loading doses should be based on actual body weight, while maintenance dose should be based on ideal body weight to avoid toxicity.

Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, and extrapyramidal symptoms, have been reported following ifosfamide therapy. There have also been reports of peripheral neuropathy associated with ifosfamide Episodes of depressive psychoses and hallucinations have been reported during ifosfamide therapy. These neurological symptoms are usually reversible, but ifosfamide should be discontinued and supportive care maintained until symptoms completely resolve. Therapy with ifosfamide should be administered cautiously in patients with a history of or predisposition to psychotic episodes.

Benzodiazepines depress the central nervous system and may cause or exacerbate mental depression and cause suicidal behavior and ideation. Episodes of mania and hypomania have also been reported in depressed patients treated with some of these agents. Therapy with benzodiazepines should be administered cautiously in patients with a history of depression or other psychiatric disorders. Patients should be monitored for any changes in mood or behavior. It may be prudent to refrain from dispensing large quantities of medication to these patients.

Paradoxical reactions, including excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams, have been reported with the use of benzodiazepines in psychiatric patients and pediatric patients with hyperactive aggressive disorders. Such patients should be monitored for signs of paradoxical stimulation during therapy with benzodiazepines. The manufacturers do not recommend the use of benzodiazepines for the treatment of psychosis.

Ifosfamide is primarily eliminated by the kidney. Approximately 12% to 18% of ifosfamide is excreted unchanged in the urine. Additionally, iIfosfamide is both nephrotoxic and urotoxic. Hemorrhagic cystitis due to metabolites excreted in the urine can develop during therapy with ifosfamide. Adequate hydration and use of a prophylactic agent such as mesna prior to each course of ifosfamide therapy can reduce bladder irritation and hematuria. Clinical signs of renal toxicity such as elevation in BUN or serum creatinine or decrease in creatinine clearance have been reported. Therapy with ifosfamide should be administered cautiously in patients with a history of or predisposition to cystitis or impaired renal function. Close clinical monitoring of serum and urinary chemistries is recommended.