DRUG INTERACTIONS- summary

 Sensitive CYP1A2 and CYP2D6 Substrates:                                                               Avoid concomitant use with CYP1A2 and CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities.

 DRUG INTERACTIONS

1. Effect of GIVLAARI on Other Drugs Sensitive CYP1A2 and CYP2D6 Substrates Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates.

Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates, for which minimal concentration changes may lead to serious or life-threatening toxicities.

If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling. 

 Hepatic Toxicity:                                                                                                      Inform patients that transaminase elevations may occur, and that laboratory testing will be conducted in the first 6 months of treatment and as clinically indicated thereafte

 ADVERSE REACTIONS

 The most common adverse reactions (=20% of patients) included nausea and injection site reactions. 

 PATIENT COUNSELING INFORMATION

Advise patients of the potential risks of GIVLAARI treatment: 

Anaphylactic Reaction:                                                                                            Inform patients about the risk and possible symptoms of severe hypersensitivity reactions that could occur 

 Hepatic Toxicity:                                                                                                      Inform patients that transaminase elevations may occur, and that laboratory testing will be conducted in the first 6 months of treatment and as clinically indicated thereafter 

 Renal Toxicity:                                                                                                            Inform patients that increases in serum creatinine and decreases in eGFR have been reported and that laboratory testing will be conducted as clinically indicated

 Injection Site Reactions:                                                                                         Inform patient of the signs and symptoms of injection site reactions (examples include redness, pain, itching, rash, discoloration, or localized swelling) 

Manufactured for:

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142 Manufactured by: Ajinomoto Althea, Inc., 11049 Roselle Street, San Diego, CA 92121

CLINICAL PHARMACOLOGY

1. Mechanism of Action                                                                                           Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA.

This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.

2. Pharmacodynamics                                                                                                  The pharmacodynamic effects of GIVLAARI were evaluated in chronic high excreters treated with 0.035 to 2.5 mg/kg single dose and AHP patients treated with 2.5 to 5 mg/kg once monthly and 2.5 to 5 mg/kg once quarterly dose via subcutaneous injection.

Dose-dependent reduction in urinary ALAS1 mRNA, ALA and PBG levels was observed over the 0.035 to 5 mg/kg dose range (0.14 to 2-fold the approved recommended dosage).

Median reductions from baseline in urinary ALA and PBG of 83.7% and 75.1%, respectively, were observed 14 days after the first dose of GIVLAARI 2.5 mg/kg once monthly in AHP patients.

Maximal reductions in ALA and PBG levels were achieved around Month 3, with median reductions from baseline of 93.8% for ALA and 94.5% for PBG, and were sustained thereafter with repeated once monthly dosing.

Cardiac Electrophysiology                                                                                          The effect of GIVLAARI on the QTc interval was evaluated in a double-blind, placebo-controlled study and the open-label extension in 94 patients. No large mean increase in QTc (i.e. >20 ms) was detected at the 2.5 mg/kg once monthly dose level. A dedicated thorough QT study has not been conducted with GIVLAARI.

3. Pharmacokinetics                                                                                                        The pharmacokinetics of givosiran and its active metabolite [AS(N-1)3'givosiran] were evaluated following single and multiple dosing in chronic high excreter subjects and AHP patients.

. Pharmacokinetic Parameters of Givosiran and Its Active Metabolite Givosiran AS(N-1)3'Givosiran General Information Steady-State Exposure Cmax [Mean (CV%)] 321 ng/mL (51%) 123 ng/mL (64%) AUC24 [Mean (CV%)] 4130 ng?h/mL (43%) 1930 ng?h/mL (63%)

Distribution                                                                                                                 (Vz/F) [Mean (RSE%)]a 10.4 L (2.3%) Protein Binding 90%b Not evaluated Organ Distribution Givosiran and AS(N-1)3'givosiran distribute primarily to the liver after subcutaneous dosing.

Elimination                                                                                                                   Half-Life [Mean (CV%)] 6 hours (46%) 6 hours (41%) Apparent Clearance [Mean (CV%)]a 35.1 L/hr (18%) 64.7 L/hr (33%)

Metabolism                                                                                                               Primary Pathway Givosiran is metabolized by nucleases to oligonucleotides of shorter lengths. Givosiran is not a substrate of CYP enzymesc .

Active Metabolite The active metabolite, AS(N-1)3'givosiran, is equipotent to givosiran in plasma and the AUC0-24 represents 45% of givosiran AUC, at the approved recommended givosiran dosage.

Excretion                                                                                                                   Primary Pathway The dose recovered in urine was 5%-14% as givosiran and 4%-13% as AS(N-1)3'givosirand .                                                                                                     a Based on population PK model estimation.                                                                     b Givosiran plasma protein binding was concentration-dependent and decreased with increasing givosiran concentrations (from 92% at 1 µg/mL to 21% at 50 µg/mL).              c Based on in vitro study result.                                                                                          d After single and multiple subcutaneous doses of givosiran 2.5 mg/kg and 5 mg/kg. 

Specific Populations                                                                                                      No clinically meaningful differences in givosiran pharmacokinetics or pharmacodynamics (percent reduction in urinary ALA and PBG) were observed based on age (19 to 65 years), sex, race/ethnicity, mild, moderate or severe renal impairment (eGFR =15 to ?89 mL/min/1.73m2 estimated by the Modification of Diet in Renal Disease [MDRD] formula), and mild hepatic impairment (bilirubin =1×ULN and AST >1×ULN, or bilirubin >1×ULN to 1.5×ULN).

The effect of end-stage renal disease (eGFR <15 mL/min/1.73m2 ), and moderate to severe hepatic impairment on givosiran pharmacokinetics is unknown.

Drug Interaction Studies                                                                                          Clinical Studies Effect of givosiran on CYP1A2 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased caffeine (sensitive CYP1A2 substrate) AUC by 3.1-fold and Cmax by 1.3-fold.

Effect of givosiran on CYP2D6 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased dextromethorphan (sensitive CYP2D6 substrate) AUC by 2.4-fold and Cmax by 2.0-fold [see Drug Interactions (7.1)].

Effect of givosiran on other CYP450 Substrates: Concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg increased losartan (CYP2C9 substrate) AUC by 1.1-fold with no change in Cmax; increased omeprazole (sensitive CYP2C19 substrate) AUC by 1.6-fold and Cmax by 1.1-fold; increased midazolam (sensitive CYP3A4 substrate) AUC by 1.5-fold and Cmax by 1.2-fold.

These changes in exposure were not considered clinically relevant. In Vitro Studies

Effect of givosiran on CYP450 Enzymes: In vitro studies indicate that givosiran does not directly inhibit or induce CYP enzymes; however, because of its pharmacological effects on the hepatic heme biosynthesis pathway, givosiran has the potential to reduce the activity of CYP enzymes in the liver. 

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                       In animal reproduction studies, subcutaneous administration of givosiran to pregnant rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity 

There are no available data with GIVLAARI use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Consider the benefits and risks of  GIVLAARI for the mother and potential adverse effects to the fetus when prescribing GIVLAARI to a pregnant woman.

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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

2. Lactation Risk Summary                                                                                              There are no data on the presence of GIVLAARI 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 GIVLAARI and any potential adverse effects on the breastfed child from GIVLAARI or from the underlying maternal condition.

4. Pediatric Use                                                                                                         Safety and effectiveness in pediatric patients have not been established.

5. Geriatric Use                                                                                                        Clinical studies of GIVLAARI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.