Interactions between Covera-HS and Palbociclib

GENERALLY AVOID: Consumption of large quantities of grapefruit juice may be associated with significantly increased plasma concentrations of oral verapamil. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. One study reported no significant effect of a single administration of grapefruit juice on the pharmacokinetics of verapamil in ten hypertensive patients receiving chronic therapy. In another study conducted in nine healthy male volunteers, administration of 120 mg oral verapamil twice daily for 3 days following pretreatment with 200 mL grapefruit juice twice daily for 5 days resulted in a 57% increase in S-verapamil peak plasma concentration (Cmax), a 36% increase in S-verapamil systemic exposure (AUC), a 40% increase in R-verapamil Cmax, and a 28% increase in R-verapamil AUC compared to administration following orange juice. Elimination half-life and renal clearance of both S- and R-verapamil were not affected by grapefruit juice, and there were no significant effects on blood pressure, heart rate, or PR interval. A third study reported a 1.63-fold increase in Cmax and a 1.45-fold increase in AUC of (R,S)-verapamil in 24 young, healthy volunteers given verapamil sustained-release 120 mg twice daily for 7 days with 250 mL grapefruit juice four times daily on days 5 through 7. Two subjects developed PR interval prolongation of more than 350 ms during grapefruit juice coadministration. A high degree of interindividual variability has been observed in these studies. The interaction was also suspected in a case report of a 42-year-old woman who developed complete heart block, hypotension, hypoxic respiratory failure, severe anion gap metabolic acidosis, and hyperglycemia following accidental ingestion of three verapamil sustained-release 120 mg tablets over a span of six hours. The patient's past medical history was remarkable only for migraine headaches, for which she was receiving several medications including verapamil. Prior to admission, the patient had a 2-week history of poorly controlled migraine, and the six hours preceding hospitalization she suffered from worsening headache and palpitations progressing to altered sensorium. An extensive workup revealed elevated verapamil and norverapamil levels more than 4.5 times above the upper therapeutic limits. These levels also far exceeded those reported in the medical literature for patients taking verapamil 120 mg every 6 hours, or 480 mg in a 24-hour period. The patient recovered after receiving ventilator and vasopressor support. Upon questioning, it was discovered that the patient had been drinking large amounts of grapefruit juice (3 to 4 liters total) the week preceding her admission due to nausea. No other sources or contributing factors could be found for the verapamil toxicity.

MANAGEMENT: Patients treated with oral verapamil should avoid the consumption of large amounts of grapefruit or grapefruit juice to prevent any undue fluctuations in serum drug levels. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the systemic exposure to palbociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to palbociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, asthenia, peripheral neuropathy, and epistaxis.

ADJUST DOSING INTERVAL: Food may enhance the oral bioavailability of palbociclib capsules and reduce the intersubject variability of palbociclib exposure. According to the product labeling, absorption and exposure of palbociclib from its oral capsule formulation were very low in approximately 13% of the population when taken in the fasted state. Food intake increased the palbociclib exposure in this small subset of the population but did not alter exposure in the rest of the population to a clinically relevant extent. Compared to palbociclib capsules given under overnight fasted conditions, the population average palbociclib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 38% and 21%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories; 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively); by 27% and 12%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories; 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively); and by 24% and 13%, respectively, when given with moderate-fat, standard calorie food (approximately 500 to 700 calories; 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) one hour before and two hours after palbociclib capsule dosing.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice while on treatment with palbociclib. To avoid variability in drug absorption between doses, palbociclib capsules should be taken with food. Palbociclib tablet formulations may be taken with or without food.

GENERALLY AVOID: Verapamil may increase the blood concentrations and intoxicating effects of ethanol. The exact mechanism of interaction is unknown but may involve verapamil inhibition of ethanol metabolism. In 10 healthy, young volunteers, verapamil (80 mg orally every 8 hours for 6 days) increased the mean peak blood concentration (Cmax) and the 12-hour area under the concentration-time curve (AUC) of ethanol (0.8 g/kg single oral dose) by 17% and 30%, respectively, compared to placebo. Verapamil AUCs were positively correlated to increased ethanol blood AUC values. Subjectively (i.e. each subject's perception of intoxication as measured on a visual analog scale), verapamil also significantly increased the area under the ethanol effect versus time curve but did not change the peak effect or time to peak effect.

MANAGEMENT: Patients treated with verapamil should be counseled to avoid alcohol consumption.

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

The use of some calcium channel blockers (CCBs) is contraindicated in patients with advanced aortic stenosis. CCBs whose pharmacologic effect is partially dependent on their ability to reduce afterload (e.g., diltiazem, nicardipine, nifedipine, verapamil) may be of less benefit in these patients due to a fixed impedance to flow across the aortic valve and may, in fact, worsen rather than improve myocardial oxygen balance. Rarely, heart failure has developed following the initiation of these CCBs, particularly in patients receiving concomitant beta-blocker therapy.

In general, calcium channel blockers (CCBs) should not be used in patients with hypotension (systolic pressure < 90 mm Hg) or cardiogenic shock. Due to potential negative inotropic and peripheral vasodilating effects, the use of CCBs may further depress cardiac output and blood pressure, which can be detrimental in these patients. The use of verapamil and diltiazem is specifically contraindicated under these circumstances.

The use of verapamil is contraindicated in patients with severe left ventricular dysfunction (e.g., ejection fraction < 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Likewise, verapamil should not be given to patients with acute myocardial infarction and pulmonary congestion documented by X-ray on admission, since associated heart failure may be acutely worsened. Verapamil has a negative inotropic effect, which in most patients is compensated by a simultaneous reduction in afterload (i.e. decreased systemic vascular resistance) without a net impairment of ventricular performance. However, congestive heart failure or pulmonary edema have developed in approximately 2% of patients treated with verapamil. Mild symptoms of cardiac failure should be under control, if possible, prior to initiating verapamil therapy.

The use of some calcium channel blockers (CCBs) is contraindicated in patients with severe bradyarrhythmia, sick sinus syndrome (unless a functioning pacemaker is present), or heart block greater than the first degree (unless a functioning pacemaker is present). CCBs like bepridil, diltiazem and verapamil have a negative effect on AV conduction and the SA node and may exacerbate these conditions.

The use of verapamil in patients with hypertrophic cardiomyopathy, or idiopathic hypertrophic subaortic stenosis, has been associated with serious side effects such as pulmonary edema, severe hypotension, sinus bradycardia, AV block, sinus arrest, and death. However, a causal relationship has not been established. Therapy with verapamil should be administered cautiously in patients with hypertrophic cardiomyopathy. Dosage reduction or drug discontinuation may be required if severe adverse effects occur.

In general, calcium channel blockers (CCBs) should not be used in patients with hypotension (systolic pressure < 90 mm Hg) or cardiogenic shock. Due to potential negative inotropic and peripheral vasodilating effects, the use of CCBs may further depress cardiac output and blood pressure, which can be detrimental in these patients. The use of verapamil and diltiazem is specifically contraindicated under these circumstances.

Increased frequency, duration, and/or severity of angina, as well as acute myocardial infarction, have rarely developed during initiation or dosage increase of calcium channel blockers (CCBs), particularly in patients with severe obstructive coronary artery disease and those treated with immediate-release formulations. The mechanism of this effect is not established. Therapy with CCBs should be administered cautiously in patients with significant coronary artery disease.

Calcium channel blockers (CCBs) are extensively metabolized by the liver. The half-lives of CCBs may be prolonged substantially in patients with severe hepatic impairment, with the potential for significant drug accumulation. In addition, the use of some CCBs has been associated with elevations in serum transaminases, both with and without concomitant elevations in alkaline phosphatase and bilirubin. While these effects may be transient and reversible, some patients have developed cholestasis or hepatocellular injury. Therapy with CCBs should be administered cautiously and often at reduced dosages in patients with significantly impaired hepatic function. Periodic monitoring of liver function is advised.

The use of verapamil is contraindicated in patients with severe left ventricular dysfunction (e.g., ejection fraction < 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Likewise, verapamil should not be given to patients with acute myocardial infarction and pulmonary congestion documented by X-ray on admission, since associated heart failure may be acutely worsened. Verapamil has a negative inotropic effect, which in most patients is compensated by a simultaneous reduction in afterload (i.e. decreased systemic vascular resistance) without a net impairment of ventricular performance. However, congestive heart failure or pulmonary edema have developed in approximately 2% of patients treated with verapamil. Mild symptoms of cardiac failure should be under control, if possible, prior to initiating verapamil therapy.

The use of verapamil is contraindicated for the management of atrial flutter or fibrillation in patients with an accessory AV tract (e.g., those with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome). Intravenous verapamil has been reported to cause ventricular fibrillation and cardiac arrest in such patients, the mechanism of which is related to the drug's ability to shorten the refractory period and accelerate antegrade conduction within the accessory pathway. Although these events have not been associated with chronic use of oral verapamil, a similar risk may exist.

The use of some calcium channel blockers (CCBs) is contraindicated in patients with severe bradyarrhythmia, sick sinus syndrome (unless a functioning pacemaker is present), or heart block greater than the first degree (unless a functioning pacemaker is present). CCBs like bepridil, diltiazem and verapamil have a negative effect on AV conduction and the SA node and may exacerbate these conditions.

The use of intravenous diltiazem or verapamil is contraindicated in patients with ventricular tachycardia. IV administration of a calcium channel blocker can precipitate cardiac arrest in such patients. Marked hemodynamic deterioration and ventricular fibrillation have occurred in patients with wide-complex ventricular tachycardia (QRS >= 0.12 seconds) treated with IV verapamil.

The use of palbociclib may cause neutropenia, including febrile neutropenia and neutropenic sepsis. It is recommended to monitor complete blood counts prior to starting treatment and at the beginning of each therapy cycle with palbociclib, as well as on Day 15 of the first 2 cycles, and as clinically indicated thereafter. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Care and close monitoring is recommended, in particular for any episodes of fever.

The controlled-onset, extended-release formulation of verapamil (Covera-HS) contains a non-deformable material. There have been rare reports of obstructive symptoms in patients with known strictures following the ingestion of similar sustained-release products. Therapy with the controlled-onset, extended-release formulation of verapamil should be administered cautiously in patients with preexisting severe gastrointestinal narrowing or obstruction, whether pathologic or iatrogenic.

The use of certain multikinase inhibitors has been associated with pulmonary toxicity. Serious cases of interstitial lung disease (ILD), including fatal cases and interstitial pneumonitis or pulmonary fibrosis have been reported. Caution is recommended when using these agents in patients with a history of interstitial pneumonitis or pulmonary fibrosis or those patients presenting with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, these agents should be permanently discontinued and appropriate measures should be instituted. Treatment should be immediately withheld in patients diagnosed with ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

Based on a population pharmacokinetic analysis with palbociclib mild hepatic impairment had no effect on the exposure of palbociclib. Close monitoring is recommended when using this agent in patients with moderate or severe hepatic impairment as the pharmacokinetics of palbociclib have not been studied in these patients. Dose modification of concomitant medications may be needed based of hepatic impairment.

Verapamil has been reported to decrease neuromuscular transmission in patients with Duchenne's muscular dystrophy and to prolong recovery from the neuromuscular blocking agent, vecuronium. Therapy with verapamil should be administered cautiously in patients with attenuated neuromuscular transmission or myopathy, since these conditions may be exacerbated. A reduced dosage may be appropriate.

Verapamil has been reported to decrease neuromuscular transmission in patients with Duchenne's muscular dystrophy and to prolong recovery from the neuromuscular blocking agent, vecuronium. Therapy with verapamil should be administered cautiously in patients with attenuated neuromuscular transmission or myopathy, since these conditions may be exacerbated. A reduced dosage may be appropriate.

The use of palbociclib may cause neutropenia, including febrile neutropenia and neutropenic sepsis. It is recommended to monitor complete blood counts prior to starting treatment and at the beginning of each therapy cycle with palbociclib, as well as on Day 15 of the first 2 cycles, and as clinically indicated thereafter. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Care and close monitoring is recommended, in particular for any episodes of fever.

Pre/perimenopausal women treated with the combination palbociclib plus fulvestrant therapy should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards. Care and close monitoring is recommended.

The use of certain multikinase inhibitors has been associated with pulmonary toxicity. Serious cases of interstitial lung disease (ILD), including fatal cases and interstitial pneumonitis or pulmonary fibrosis have been reported. Caution is recommended when using these agents in patients with a history of interstitial pneumonitis or pulmonary fibrosis or those patients presenting with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, these agents should be permanently discontinued and appropriate measures should be instituted. Treatment should be immediately withheld in patients diagnosed with ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

Approximately 70% of an administered dose of verapamil is excreted as metabolites in the urine. The primary metabolite, norverapamil, has about 20% the cardiovascular activity and can reach steady-state plasma concentrations approaching those of the parent drug. Patients with impaired renal function may be at greater risk for adverse effects due to drug and metabolite accumulation. Therapy with verapamil should be administered cautiously in such patients, with appropriate monitoring for excessive pharmacologic effects (e.g., abnormal prolongation of PR interval) and the dosage adjusted accordingly as necessary.

Based on a population pharmacokinetic analysis with palbociclib mild and moderate renal impairment had no effect on the exposure of palbociclib. Close monitoring is recommended when using this agent in patients with severe renal impairment as the pharmacokinetics of palbociclib in these patients have not been studied.