Nymalize (nimodipine)

No dosing information is available for this tab.

Nimodipine is administered orally only (as capsules or an oral solution). The manufacturer recommends administration at least 1 hour before or 2 hours after meals.

Nimodipine has been administered by IV infusion+ (IV dosage form currently not commercially available in the US) and by intracisternal+ or intraventricular+ surgical application of a nimodipine sustained-release microparticle formulation (dosage form currently not commercially available in the US) in patients with subarachnoid hemorrhage. The manufacturer states that the contents of nimodipine capsules or nimodipine oral solution must not be administered IV or by any other parenteral route; death and serious, life-threatening adverse effects such as cardiac arrest, cardiovascular collapse, hypotension, and bradycardia have occurred with such administration.

Nimodipine oral solution may be administered orally or into a nasogastric or gastric tube following transfer into a designated oral syringe. To minimize administration errors, the syringe should be labeled for oral use only; not for IV use. Refill the oral syringe with 0.9% sodium chloride solution and then flush any remaining contents from the nasogastric or gastric tube into the stomach. Consult the manufacturer's administration instructions for the appropriate volume of flush solution.

If the oral capsule cannot be swallowed (e.g., when administered at the time of surgery or to an unconscious patient) and the oral solution is not available, the liquid-filled capsule may be punctured at both ends with an 18-gauge needle and the contents transferred to an oral syringe that cannot accept a needle and that is designed for naso-gastric or percutaneous endoscopic gastrostomy (PEG) tube administration. To minimize administration errors, the syringe should be labeled for oral use only; not for IV use. The contents of the capsule should then be administered via the patient's nasogastric tube. Following administration, the tubing should be flushed with 30 mL of 0.9% sodium chloride solution.

Nimodipine capsules should be protected from light by storing them in the manufacturer's original unit-dose foil packaging; the capsules also should be protected from freezing and stored at 20-25degreesC (excursions permitted to 15-30degreesC).

Nimodipine 3 and 6 mg/mL oral solution should be stored at 20-25degreesC (excursions permitted to 15-30degreesC); do not refrigerate the oral solution and protect it from light and freezing.

No dosing information is available for this tab.

Nimodipine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Inhibitors and inducers of these isoenzymes may reduce or increase nimodipine clearance, respectively.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Nifedipine; Nimodipine; Nisoldipine/Slt Strong 3A4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may induce the CYP3A4 mediated metabolism of nifedipine,(1) and nimodipine,(2,3) and nisoldipine.(4) Nisoldipine is particularly susceptible to changes in CYP3A4 activity.(4,5)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may result in decreased levels and effectiveness of nifedipine(1), nimodipine or nisoldipine.(6)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Due to the risk for treatment failure, use an alternative agent if possible. The US manufacturer of nifedipine states that the concurrent use of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated because efficacy could be significantly reduced.(1) The UK manufacturer of nimodipine states that the concurrent use of carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated.(2) The US manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers should generally be avoided due to decreased nimodipine plasma concentrations and significantly reduced efficacy.(6) The US manufacturer of nisoldipine states it should generally not be coadministered with CYP3A4 inducers. Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7)

DISCUSSION: Coadministration of phenytoin with nifedipine (10 mg capsule and 60 mg extended-release tablet) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of nifedipine by 70%.(1) A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1), and epileptic patients taking valproic acid (n=8). In patients taking enzyme-inducing anticonvulsants, nimodipine AUC, Cmax, and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls. In patients taking valproic acid, nimodipine AUC was 54.5% higher than in control patients.(3) Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7) In a study comparing patients receiving chronic phenytoin therapy to healthy controls, phenytoin decreased the AUC of a single dose of nisoldipine by 89%.(8)

Nimodipine/Selected Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of strong CYP3A4 inducers may induce the metabolism of nimodipine.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of nimodipine.(1,2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The UK manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers is contraindicated.(1) The US manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers should be avoided.(2)

DISCUSSION: A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1). In patients taking enzyme-inducing anticonvulsants, nimodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls.(2) Strong CYP3A4 inducers linked include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifampin, rifapentine, and St. Johns wort.(3)

Nimodipine/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nimodipine is metabolized by CYP3A4. Strong inhibitors of CYP3A4 may decrease the metabolism of nimodipine.(1-3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels of and toxicity from nimodipine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of nimodipine capsules states that the concurrent use of strong CYP3A4 inhibitors is contraindicated due to the risk of significant hypotension.(1) The US manufacturer of nimodipine solution states that strong CYP3A4 inhibitors should generally be avoided.(2) The US manufacturers of some strong CYP3A4 inhibitors, including cobicistat(4) and ritonavir,(5) state that concurrent use of CYP3A4 substrates for which increased levels may cause serious or life-threatening events are contraindicated. If coadministration is necessary, monitor the patient closely and adjust the dose of nimodipine as needed.(3)

DISCUSSION: In 7 healthy volunteers, cimetidine (a moderate CYP3A4 inhibitor) 200 mg 3 times daily with meals and 400 mg at bedtime increased the area-under-curve (AUC) and maximum concentration (Cmax) of nimodipine (30 mg 3 times daily) by 82% and 54%, respectively. There was no change in blood pressure, heart rate, or tolerability of nimodipine, and no dose adjustment was required.(6) The combination of nimodipine with strong CYP3A4 inhibitors has not been studied, but a more marked effect is expected. Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(7-8)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Calcium Channel Blockers/Dantrolene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Dantrolene may decrease the release of calcium from the sarcoplasmic reticulum, resulting in additive or synergistic effects with calcium channel blockers.(1)

CLINICAL EFFECTS: Concurrent use of dantrolene and calcium channel blockers may result in cardiogenic shock.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US, UK, and Australian manufacturers of dantrolene state that concurrent use with calcium channel blockers during the management of malignant hyperthermia crisis is not recommended.(2-4) The Australian and UK manufacturers of diltiazem state that concurrent use of dantrolene infusion with calcium channel blockers is contraindicated.(5-6)

DISCUSSION: Cardiogenic shock in patients treated simultaneously with verapamil and dantrolene is rare but has been reported.(2-4,7) Concurrent use of dantrolene and verapamil in swine has been reported to result in cardiogenic shock and hyperkalemia.(8) In dogs, the combination has been reported to cause hyperkalemia.(9) The combination of diltiazem and dantrolene has been reported to cause adverse cardiovascular effects in swine.(10) A study in swine showed no adverse effects from the combination of dantrolene and nifedipine(10) and one patient who experience cardiogenic shock with dantrolene and verapamil had no adverse effects with the combination of dantrolene and nifedipine;(7) however, the US manufacturer cannot endorse the safety of the combination.(2)

Selected Inhibitors Of Cnt Or Ent/Cladribine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of concentrative nucleoside transporters (CNT) or equilibrative nucleoside transporters (ENT) may increase the absorption of cladribine.(1-2)

CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of CNT or ENT may result in elevated levels of cladribine and signs of toxicity.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of CNT or ENT inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the CNT or ENT inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored.

DISCUSSION: Cladribine is a substrate of CNT and ENT. Inhibitors of these transporters are expected to increase cladribine levels.(1-2) Nucleoside inhibitors linked to this monograph include: cilostazol, dipyridamole, nifedipine, nimodipine, reserpine, and sulindac.(1-2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Nimodipine/Valproic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproic acid may inhibit the metabolism of nimodipine.(1)

CLINICAL EFFECTS: Concurrent use of valproic acid may result in increased levels of and toxicity from nimodipine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking valproic acid may required reduced dosages of nimodipine.(1)

DISCUSSION: A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1), and epileptic patients taking valproic acid (n=8). In patients taking enzyme-inducing anticonvulsants, nimodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls. In patients taking valproic acid, nimodipine AUC was 54.5% higher than in control patients.(1)

Selected Antihypertensive Agents/Selected Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

*Concomitant use with strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g., clarithromycin, nelfinavir, ritonavir, ketoconazole, itraconazole, voriconazole, nefazodone) due to the risk of significant hypotension.

There are no contraindication contraindications for this drug.

• Chronic idiopathic constipation
• Severe hypotension

• Disease of liver

Most common reported adverse reactions were hypotension, headache, nausea, and bradycardia.

More Frequent

• Bradycardia
• Hypotension

Less Frequent

• Peripheral edema

Rare or Very Rare

• Abnormal ECG
• Allergic dermatitis
• Chronic heart failure
• Depression
• Pulmonary edema
• Skin rash
• Tachycardia
• Thrombocytopenic disorder

More Frequent

• Headache disorder
• Nausea

Less Frequent

• Diarrhea
• Myalgia

Rare or Very Rare

• Acne vulgaris
• Cramps
• Dizziness
• Edema
• Flushing

No enhanced messaging available.

Safety and efficacy of nimodipine in children younger than 18 years of age have not been established.

There are no adequate and controlled studies evaluating use of nimodipine in pregnant women. Nimodipine at oral (gavage) dosages of 1 (less than the recommended human dose (RHD) of 360 mg/day on a body surface area (mg/m2) basis) or 10 mg/kg daily, but not at 3 mg/kg daily, was associated with an increased incidence of malformations and stunted fetal growth when given from day 6 through day 18 of pregnancy in rabbits. In a second study, an increased incidence of stunted fetal growth was observed at oral dosages of 1 mg/kg daily but not at the higher dosages. Nimodipine was embryotoxic in rats at oral dosages of 100 mg/kg daily (approximately 3 times the RHD on a mg/m2 basis), causing resorption or stunted fetal growth when administered by gavage from day 6 through 15 of pregnancy. Slight maternotoxicity was observed in one of these studies but may have been attributable to the presence of polyethylene glycol 400 in the gavage solution. When administered in 2 other studies to rats at oral dosages of 30 mg/kg daily (dose similar to the RHD on a mg/m2 basis) from day 16 of gestation until sacrifice (at day 20 of pregnancy or day 21 postpartum), nimodipine was associated with higher incidences of skeletal variation, stunted fetal growth, and stillbirths, but no malformations. In addition, the drug did not impair postnatal development.

Nimodipine should be used during pregnancy only when the potential benefits justify the risks to the fetus.

Nimodipine has been detected in human milk; however, it is not known whether the drug has any effects on milk production or on the breastfed infant. Nimodipine and/or its metabolites are distributed into milk in animals (rats) in concentrations much higher than those in maternal plasma.

Consider the mother's clinical need for nimodipine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

The manufacturer recommends cautious dosage selection in geriatric patients, reflecting the greater frequency of decreased hepatic, renal and/or cardiac function, and of concomitant disease or other drug therapy.

The manufacturers state that clinical studies of nimodipine did not include a sufficient number of patients 65 years of age or older to determine whether such patients respond differently than younger individuals, but that other reported clinical experience has not identified differences in response between geriatric and younger patients. In a pharmacokinetic study, peak plasma concentrations and AUC of nimodipine were about twice as high in geriatric individuals as in younger individuals following single and multiple dosing; however, no clinically important age-related differences in response were noted. An appropriate dosage of nimodipine in geriatric patients should be selected with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in these patients.