DRUG INTERACTIONS

Concomitant Use of Anticoagulants Concomitant use of CABLIVI with any anticoagulant may increase the risk of bleeding. Assess and monitor closely for bleeding with concomitant use 

BRIEF SUMMARY

CAPLACIZUMAB-yhdp- ( Feb 2019)

Indn-  To treat adult patients with acquired thrombocylopenic purpura(aTTP)

Comp-  For injection: 11 mg as a lyophilized powder in a single-dose vial.

 ADR- Most common adverse reactions (incidence >15%) are epistaxis, headache, and gingival bleeding. 

CI-   o First day of treatment:                                                                                                11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1. 

o Subsequent treatment  during daily plasma exchange:                                                11 mg subcutaneous injection once daily following plasma exchange. 

Pat inform-                                                                                                                 Bleeding                                                                                                                      Advise patients that bruising and bleeding may occur more easily, that nose bleeds and bleeding of gums may occur, and that it may take them longer than usual to stop bleeding.

=================================================================

U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  2

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                      CABLIVI® safely and effectively.

See full prescribing information for CABLIVI. CABLIVI (caplacizumab-yhdp) for injection, for intravenous or subcutaneous use

Initial U.S. Approval: 2019

INDICATIONS AND USAGE

CABLIVI is a von Willebrand factor (vWF)-directed antibody fragment indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

DOSAGE AND ADMINISTRATION

CABLIVI should be administered upon the initiation of plasma exchange therapy. The recommended dose of CABLIVI is as follows:

 o First day of treatment:                                                                                                11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.

o Subsequent treatment  during daily plasma exchange:                                                11 mg subcutaneous injection once daily following plasma exchange.       

 o Treatment after the plasma exchange period:                                                         11 mg subcutaneous injection once daily for 30 days beyond the last plasma exchange.

o If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.

o Discontinue CABLIVI if the patient experiences more than 2 recurrences of aTTP, while on CABLIVI.  The first dose should be administered by a healthcare provider as a bolus

ADVERSE REACTIONS

 Most common adverse reactions (incidence >15%) are epistaxis, headache, and gingival bleeding. 

CONTRAINDICATIONS

 Previous severe hypersensitivity reaction to caplacizumab-yhdp or any of the excipients. 

WARNINGS AND PRECAUTIONS

Bleeding: Severe bleeding can occur; risk is increased in patients with underlying coagulopathies. If clinically significant bleeding occurs, interrupt treatment. Withhold CABLIVI 7 days prior to elective surgery, dental procedures, or other invasive interventions.

INDICATIONS AND USAGE

CABLIVI is a von Willebrand factor (vWF)-directed antibody fragment indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

DOSAGE AND ADMINISTRATION

CABLIVI should be administered upon the initiation of plasma exchange therapy. The recommended dose of CABLIVI is as follows: 

 o First day of treatment:                                                                                                11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1. 

o Subsequent treatment  during daily plasma exchange:                                                11 mg subcutaneous injection once daily following plasma exchange.        

 o Treatment after the plasma exchange period:                                                         11 mg subcutaneous injection once daily for 30 days beyond the last plasma exchange. 

o If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.

o Discontinue CABLIVI if the patient experiences more than 2 recurrences of aTTP, while on CABLIVI.  The first dose should be administered by a healthcare provider as a bolus intravenous injection. Administer subsequent doses subcutaneously in the abdomen. 

 Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Unopened vials may be stored in the original carton at room temperature up to 30°C (86°F) for a single period of up to 2 months.

Do not return CABLIVI to the refrigerator after it has been stored at room temperature.

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Bleeding                                                                                                                      Advise patients that bruising and bleeding may occur more easily, that nose bleeds and bleeding of gums may occur, and that it may take them longer than usual to stop bleeding.

Advise patients to contact their healthcare provider immediately if excessive bleeding or bruising occur.

 Advise patients to inform their healthcare provider before scheduling any elective surgery, dental procedure or other invasive interventions.

Manufactured by:

Ablynx N.V. Technologiepark 21

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF Reference ID: 4386486 and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.

2. Pharmacodynamics

Ristocetin cofactor (RICO) activity was used to assess vWF activity. Subcutaneous doses of caplacizumab-yhdp at greater than or equal to the approved recommended dosage to healthy subjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4 hours post-dose. RICO activity returned to baseline values within 7 days of drug discontinuation. Caplacizumab-yhdp decreased vWF antigen and factor VIII:C levels. These reductions were transient and returned to baseline upon cessation of treatment.

3. Pharmacokinetics

Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are not dose proportional. Higher levels of vWF antigen increase the fraction of drug-target complex retained in the circulation.

Steady-state was reached following the first administration of CABLIVI in healthy subjects, with minimal accumulation.

Following a single subcutaneous dose of 10 mg caplacizumab-yhdp to healthy subjects the mean (CV%) peak concentration (Cmax) was 528 (20%) ng/ml and AUC0-24 was 7951 (16%).

Following subcutaneous dosing of 10 mg caplacizumab-yhdp daily for 14 days to healthy subjects, the mean (CV%) Cmax was 348 (30%) ng/ml and AUC0-t was 6808 (26%) hr·ng/ml.

Absorption                                                                                                                    The bioavailability of subcutaneous caplacizumab-yhdp is approximately 90%. The maximum concentration was observed 6 to 7 hours after subcutaneous dosing of 10 mg caplacizumab-yhdp once daily in healthy subjects. 

Distribution                                                                                                            Caplacizumab-yhdp central volume of distribution is 6.33 L in patients with aTTP.

Elimination                                                                                                                         The half-life of caplacizumab-yhdp is concentration and target-level dependent.

Metabolism                                                                                                                     The available data suggest target-bound caplacizumab-yhdp is metabolized within the liver. Because caplacizumab-yhdp is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes.

Excretion                                                                                                                           The available nonclinical data suggest unbound caplacizumab-yhdp is cleared renally.

Antidrug Antibodies No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed in patients with pre-existing or treatment-emergent anti-drug antibodies.

Specific Populations

No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed based on age (18 to 79 years), sex (66% females), race (White (83%) and Black Reference ID: 4386486 (17%)), blood group (O (41%) and other groups (59%)), or renal impairment (mild [CrCl: 60 to 90 mL/min], moderate [CrCl: 30 to 60 mL/min] or severe [CrCl: 15 to 30 mL/min]).

The effect of hepatic impairment on the pharmacokinetics of caplacizumab-yhdp is unknown 

Drug Interaction Studies No dedicated drug-drug interaction studies with caplacizumab-yhdp have been conducted.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

There are no available data on CABLIVI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. However, there are potential risks of hemorrhage in the mother and fetus associated with use of CABLIVI 

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown.

In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/neonatal adverse reactions CABLIVI may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding

 Maternal adverse reactions All patients receiving CABLIVI, including pregnant women, are at risk for bleeding. Pregnant women receiving CABLIVI should be carefully monitored for evidence of excessive bleeding 

2.Lactation Risk Summary

There is no information regarding the presence of caplacizumab-yhdp in human milk, the effects on the breastfed child or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CABLIVI and any potential adverse effects on the breastfed child from CABLIVI, or from the underlying maternal condition.

3 Pediatric Use

The safety and effectiveness of CABLIVI in pediatric patients have not been established.

4. Geriatric Use

Clinical studies of CABLIVI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

5. Hepatic Impairment

No formal studies with CABLIVI have been conducted in patients with severe acute or chronic hepatic impairment and no data regarding the use of CABLIVI in these populations are available.

Due to a potential increased risk of bleeding, use of CABLIVI in patients with severe hepatic impairment requires close monitoring for bleeding 

 OVERDOSAGE

In case of overdose, based on the pharmacological action of CABLIVI, there is the potential for an increased risk of bleeding 

Close monitoring for signs and symptoms of bleeding is recommended. If needed, the use of von Willebrand factor concentrate could be considered to correct hemostasis.